JP2018535931A - Novel imidazo [4,5-b] pyridine derivatives as dual DYRK1 / CLK1 inhibitors - Google Patents

Abstract

A compound of formula (I) (formula I) useful for treating cancer, neurodegenerative disorders and metabolic disorders.

Description

  The present invention relates to novel imidazo [4,5-b] pyridine derivatives, to processes for preparing them, and to pharmaceutical compositions containing them.

  The compounds according to the invention are new and have very valuable pharmacological characteristics in the field of oncology.

  The present invention relates to the use of dual DYRK1 / CLK1 inhibitors in the treatment of cancer, neurodegenerative disorders and metabolic disorders.

  In cancer, the bispecific tyrosine phosphorylation-regulated kinases DYRK1A and DYRK1B regulate several pathways that enhance cancer cell proliferation, migration and metastasis, induce resistance to cell death, and It has been shown to suppress responses to targeted anti-cancer therapies [Non-Patent Documents 1 to 4]. Reported substrates of DYRK1A involved in the regulation of cancer progression and resistance to therapy include the transcription factors GLI1, STAT3 and FOXO1 [Non-Patent Documents 5-7]. DYRK1A is thought to stabilize cancer-related tyrosine kinase receptors such as EGFR and FGFR through interaction with the protein Sprouty2 [Non-patent Documents 8 and 9]. DYRK1A and DYRK1B have also been shown to be required to induce cell quiescence in response to treatment of cancer cells with chemotherapeutic agents and targeted therapies. This is important because quiescent cancer cells are known to be relatively insensitive to most anti-cancer drugs and radiation [10, 11]. For example, DYRK1A activates the DREAM multi-subunit protein complex, which maintains cell quiescence and protects against apoptosis [12]. DYRK1B has been shown to prevent cell cycle termination in response to chemotherapy through phosphorylation of Cyclin D1 [13]. DYRK1B has also been shown to protect against chemotherapy through a reduction in the content of reactive oxygen species [14].

  Thus, if the use of a DYRK1A / DYRK1B inhibitor is either used alone or in combination with conventional therapy, radiation or targeted therapy as a strategy to combat resistance, a variety of It is clear that it constitutes a novel anti-cancer treatment in a variety of cancers.

  The role of DYRK1A in neuropathy is well established. DYRK1A is associated with neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease and Huntington's disease, as well as Down's syndrome, mental retardation and movement disorders [Non-Patent Documents 1, 15, 16]. DYRK1A has been identified as a major kinase that phosphorylates the microtubule-associated protein TAU that forms neurotoxic neurofibrillary tangles seen in Alzheimer's disease and leads to neurodegeneration [Non-Patent Document 17]. DYRK1A also alters TAU RNA precursor splicing that leads to an imbalance between TAU isoforms sufficient to cause neurodegeneration and dementia [18]. Thus, it is not surprising that DYRK1A is thought to be causally involved in the development of Alzheimer-like neurodegenerative disease in Down's syndrome patients in which 3 copies of the DYRK1A gene are present on chromosome 21. In these individuals, increased DYRK1A activity also causes premature neuronal differentiation and a decrease in mature neurons [Non-Patent Document 19].

  Thus, it is clear that the use of DYRK1A inhibitors provides a novel therapeutic approach for treating neurodegenerative disorders (particularly Alzheimer's disease) as well as other neurological conditions such as Down's syndrome.

  The CDC2-like kinase (CLK) family contains four isoforms (CLK1-4) that are important in regulating the function of the spliceosome complex [20]. This complex composed of small nuclear RNA (snRNA) and a number of related proteins regulates the splicing of the mRNA precursor to give the mRNA encoding the mature protein. CLK1 is known to regulate the activity of the spliceosome through phosphorylation of serine-arginine rich (SR) protein, which is a constituent factor [Non-patent Document 21]. By controlling the activity of the spliceosome in this way, many genes can express more than one mRNA, leading to diversity in the translated protein. Selective protein isoforms transcribed from the same gene often have different activities and physiological functions. Deregulation of alternative splicing is associated with cancer, where it is known that many cancer-related proteins are alternatively spliced [Non-Patent Document 22]. An example of a protein that is alternatively spliced in cancer is Cyclin D1, which is important for the progression of cancer cells throughout the cell cycle [23].

  Thus, the use of a CLK1 inhibitor constitutes a novel anti-cancer treatment in a wide variety of cancers, either when used alone or in combination with conventional therapy, radiation or targeted therapy. It is clear.

  Moreover, it is described that alternative splicing regulated by CLK1 plays a role in neurodegenerative diseases including Alzheimer's disease and Parkinson's disease through phosphorylation of SR protein of spliceosome [Non-patent document 24]. In the case of Alzheimer's disease, CLK1 is known to regulate alternative splicing of the microtubule-associated protein TAU that leads to an imbalance between TAU isoforms sufficient to cause neurodegeneration and dementia [non-patent literature. 18].

  Thus, it is clear that the use of CLK1 inhibitors provides a novel therapeutic approach for treating neurodegenerative disorders (particularly Alzheimer's disease) as well as other neurological conditions such as Parkinson's disease.

  Therefore, there is an urgent need for compounds that potently inhibit DYRK1 and CLK1 kinases while not affecting other closely related kinases in the treatment of both cancer and nervous system diseases. DYRK1 and CLK1 kinases are members of the CMGC group, including CDK and GSK kinases, and its chronic inhibition is believed to cause toxicity to patients. For example, the general toxicity observed in clinically observed CDK inhibition is similar to that observed with conventional cytotoxic therapy, and hepatotoxicity (leukopenia and thrombocytopenia), gastrointestinal toxicity ( Including nausea and diarrhea) and fatigue [Non-patent Document 25]. The present invention describes a new class of DYRK1 / CLK1 inhibitors that are more selective for DYRK1 and CLK1 than these other kinases and are therefore suitable for use in the treatment of these pathologies.

  Type 1 and type 2 diabetes both include a deficiency of functional pancreatic insulin-producing beta cells. Thus, recovery of functional beta cell mass is an important treatment goal for these diseases affecting 380 million people worldwide. Recent studies have shown that DYRK1A inhibition promotes human beta cell proliferation in vitro and in vivo and can increase glucose-dependent insulin secretion after prolonged treatment [Non-Patent Document 26, 27]. These findings clearly suggest that the use of potent and selective DYRK1A inhibitors provides a novel therapeutic approach for treating and / or preventing metabolic disorders including diabetes and obesity.

Abbassi et al, Pharmacol Ther., 2015; 151: 87-98 Ionescu et al, Mini Rev Med Chem., 2012; 12 (13): 1315-29 Friedman et al, J Cell Biochem., 2007; 102 (2): 274-9 Yoshida et al, Biochem Pharmacol., 2008; 76 (11): 1389-94 Mao et al, J Biol Chem., 2002; 277 (38): 35156-61 Matsuo et al, J Immunol Methods, 2001; 247: 141-51 Woods et al, Biochem J., 2001; 355 (Pt 3): 597-607 Ferron et al, Cell Stem Cell., 2010; 7 (3): 367-79 Aranda et al, Mol Cell Biol., 2008; 28 (19): 5899-911 Ewton et al, Mol Cancer Ther., 2011; 10 (11): 2104-14 Jin et al, J Biol Chem., 2009; 284 (34): 22916-25 Litovchick et al, Genes Dev., 2011; 25 (8): 801-13 Zou et al, J Biol Chem., 2004; 279 (26): 27790-8 Hu et al, Genes Cancer., 2010; 1 (8): 803-811 Beker et al, CNS Neurol Disord Drug Targets., 2014; 13 (1): 26-33 Dierssen, Nat Rev Neurosci., 2012 Dec; 13 (12): 844-58 Azorsa et al, BMC Genomics., 2010; 11:25 Liu et al, Mol Neurodegener., 2008; 3: 8 Haemmerle et al, Development., 2011; 138 (12): 2543-54 Fedorov et al, Chem Biol., 2011; 18 (1): 67-76 Bullock et al, Structure., 2009; 17 (3): 352-62 Druillennec et al, J Nucleic Acids., 2012; 2012: 639062 Wang et al, Cancer Res., 2008; 68 (14): 5628-38 Jain et al, Curr Drug Targets., 2014; 15 (5): 539-50 Kumar et al, Blood., 2015; 125 (3): 443-8 Dirice et al, Diabetes., 2016; 65 (6): 1660-71 Wang et al, Nat Med., 2015; 21 (4): 383-8

（式中、
◆Ｒ_１は、シアノ基、ハロゲン原子、又は１〜３個のハロゲン原子によって場合により置換されている直鎖若しくは分枝鎖（Ｃ_１−Ｃ_６）アルキル基を表し、
◆Ｒ_２は、水素、直鎖若しくは分枝鎖（Ｃ_１−Ｃ_６）アルキル基、直鎖若しくは分枝鎖（Ｃ_２−Ｃ_６）アルケニル基、直鎖若しくは分枝鎖（Ｃ_２−Ｃ_６）アルキニル基、Ｃｙ_１、−（Ｃ_１−Ｃ_６）アルキレン−［Ｏ］_ｎ−Ｃｙ_１基、−（Ｃ_１−Ｃ_６）アルケニレン−［Ｏ］_ｎ−Ｃｙ_１基、−（Ｃ_１−Ｃ_６）アルキレン−ＮＲ−Ｃｙ_１基、−（Ｃ_１−Ｃ_６）アルキレン−Ｓ−Ｃｙ_１基、−（Ｃ_０−Ｃ_６）アルキレン−Ｃｙ_２−Ｃｙ_１基、又は−Ｃｙ_２−（Ｃ_１−Ｃ_６）アルキレン−Ｃｙ_１基を表し、本明細書中に定義されたアルキル及びアルキレン部分は、直鎖又は分枝鎖であってもよいことが理解され、
◆Ｒは、水素、又は直鎖若しくは分枝鎖（Ｃ_１−Ｃ_６）アルキル基を表し、
◆ｎは、０又は１に等しい整数であり、
◆Ｒ_３は、水素原子、ハロゲン原子、−ＮＲ_６Ｒ_６’、−ＮＨ−（Ｃ_０−Ｃ_６）アルキレン−Ｃｙ_３、−ＮＨ−ＣＯ−（Ｃ_０−Ｃ_６）アルキレン−Ｃｙ_３、−ＮＨ−ＣＯ−（Ｃ_０−Ｃ_６）アルキレン−Ｏ−Ｃｙ_３を表し、
◆Ｒ_４及びＲ_５は、それぞれ他方とは独立して、水素又はハロゲン原子を表し、
◆Ｒ_６及びＲ_６’は、それぞれ他方とは独立して、水素、又は直鎖若しくは分枝鎖（Ｃ_１−Ｃ_６）アルキル基を表し、
◆Ｃｙ_１、Ｃｙ_２及びＣｙ_３は、互いに独立して、シクロアルキル基、ヘテロシクロアルキル基、アリール又はヘテロアリール基を表し、
「アリール」は、フェニル、ナフチル、ビフェニル又はインデニル基を意味し、
「ヘテロアリール」は、少なくとも１個の芳香族部分を有し、かつ、酸素、イオウ及び窒素から選択される１〜４個のヘテロ原子を含有する、５〜１０個の環員で構成される任意の単環式又は二環式の基を意味し、
「シクロアルキル」は、縮合、架橋又はスピロの環系を含んでもよい、３〜１１個の環員を含有する任意の単環式又は二環式の、非芳香族の、炭素環式の基を意味し、
「ヘテロシクロアルキル」は、縮合、架橋又はスピロの環系を含んでもよい、３〜１０個の環員で構成され、かつ、酸素、イオウ、ＳＯ、ＳＯ_２及び窒素から選択される１〜３個のヘテロ原子を含有する任意の単環式若しくは二環式の、非芳香族の、縮合又はスピロの基を意味し、
「−（Ｃ_０−Ｃ_６）アルキレン−」は、共有結合（−Ｃ_０アルキレン−）、又は１、２、３、４、５若しくは６個の炭素原子を含有するアルキレン基のいずれかを指す
ことが理解され、
このように定義されたアリール、ヘテロアリール、シクロアルキル及びヘテロシクロアルキル基、並びにアルキル、アルケニル、アルキニル、アルキレン、アルケニレンは、直鎖若しくは分枝鎖（Ｃ_１−Ｃ_６）アルキル、直鎖若しくは分枝鎖（Ｃ_２−Ｃ_６）アルケニル基、直鎖若しくは分枝鎖（Ｃ_２−Ｃ_６）アルキニル基、直鎖若しくは分枝鎖（Ｃ_１−Ｃ_６）アルコキシ、直鎖若しくは分枝鎖（Ｃ_１−Ｃ_６）アルキル−Ｓ−、ヒドロキシ、オキソ（又は適切な場合、Ｎ−オキシド）、ニトロ、シアノ、−Ｃ（Ｏ）−ＯＲ’、−Ｃ（Ｏ）−Ｒ’、−Ｏ−Ｃ（Ｏ）−Ｒ’、−Ｃ（Ｏ）−ＮＲ’Ｒ’’、−ＮＲ’−Ｃ（Ｏ）−Ｒ’’、−ＮＲ’Ｒ’’、直鎖若しくは分枝鎖（Ｃ_１−Ｃ_６）ポリハロアルキル、ジフルオロメトキシ、トリフルオロメトキシ又はハロゲンから選択される１〜４個の基によって置換されていることが可能であり、Ｒ’及びＲ’’は、互いに独立して、水素原子、又は置換されている直鎖若しくは分枝鎖（Ｃ_１−Ｃ_６）アルキル基を表すことが理解される）
で示される化合物に、そららのエナンチオマー及びジアステレオ異性体に、並びにそれらの薬学的に許容し得る酸又は塩基との付加塩に関する。 The present invention more particularly relates to formula (I):

(Where
R ₁ represents a cyano group, a halogen atom, or a linear or branched (C ₁ -C ₆ ) alkyl group optionally substituted by 1 to 3 halogen atoms,
◆ R ₂ is hydrogen, straight chain or branched chain (C ₁ -C ₆ ) alkyl group, straight chain or branched chain (C ₂ -C ₆ ) alkenyl group, straight chain or branched chain (C ₂ -C _{6) alkynyl,} Cy 1, - _(C 1 -C ₆₎ alkylene - _[O] n -Cy ₁ group, - _(C 1 -C ₆₎ alkenylene - _[O] n -Cy ₁ group, - _{(C 1} -C ₆₎ alkylene -NR-Cy ₁ group, - _(C 1 -C ₆₎ alkylene--S-Cy ₁ group, - _(C 0 -C ₆₎ alkylene _-Cy 2 -Cy ₁ group, or -Cy ₂ - It is understood that the alkyl and alkylene moieties that represent a (C ₁ -C ₆ ) alkylene-Cy ₁ group and are defined herein may be straight or branched chain;
◆ R represents hydrogen, or a linear or branched (C ₁ -C ₆ ) alkyl group,
◆ n is an integer equal to 0 or 1,
◆ R ₃ is a hydrogen atom, a halogen atom, —NR ₆ R ₆ ′, —NH— (C ₀ -C ₆ ) alkylene-Cy ₃ , —NH—CO— (C ₀ -C ₆ ) alkylene-Cy ₃ , _{-NH-CO- (C 0 -C 6} ) alkylene -O-Cy _3,
◆ R ₄ and R ₅ each independently represent a hydrogen or halogen atom,
R ₆ and R ₆ ′ each independently of the other represent hydrogen or a linear or branched (C ₁ -C ₆ ) alkyl group;
Cy ₁ , Cy ₂ and Cy ₃ each independently represent a cycloalkyl group, a heterocycloalkyl group, an aryl or a heteroaryl group,
“Aryl” means a phenyl, naphthyl, biphenyl or indenyl group;
“Heteroaryl” is composed of 5 to 10 ring members having at least one aromatic moiety and containing 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen Means any monocyclic or bicyclic group,
“Cycloalkyl” is any monocyclic or bicyclic, non-aromatic, carbocyclic group containing from 3 to 11 ring members, which may include fused, bridged or spiro ring systems. Means
“Heterocycloalkyl” is composed of 3 to 10 ring members which may include fused, bridged or spiro ring systems and is selected from oxygen, sulfur, SO, SO ₂ and nitrogen 1-3 Means any monocyclic or bicyclic, non-aromatic, fused or spiro group containing 1 heteroatom,
“— (C ₀ -C ₆ ) alkylene-” refers to either a covalent bond (—C ₀ alkylene-) or an alkylene group containing 1, 2, 3, 4, 5 or 6 carbon atoms. Is understood and
Aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups as defined above, as well as alkyl, alkenyl, alkynyl, alkylene, alkenylene are linear or branched (C ₁ -C ₆ ) alkyl, linear or branched Branched (C ₂ -C ₆ ) alkenyl group, linear or branched (C ₂ -C ₆ ) alkynyl group, linear or branched (C ₁ -C ₆ ) alkoxy, linear or branched ( C ₁ -C ₆₎ alkyl -S-, hydroxy, if oxo (or suitable, N- oxide), nitro, cyano, -C (O) -OR ', - C (O) -R', - O- C (O) —R ′, —C (O) —NR′R ″, —NR′—C (O) —R ″, —NR′R ″, linear or branched (C ₁ — C ₆₎ polyhaloalkyl, difluoromethoxy, trifluoromethoxy methemoglobin R ′ and R ″ can be independently of one another a hydrogen atom, or a straight or branched chain that is substituted, It is understood to represent a chain (C ₁ -C ₆ ) alkyl group)
To the enantiomers and diastereoisomers thereof, and their addition salts with pharmaceutically acceptable acids or bases.

  Among pharmaceutically acceptable acids, but not intended to be limited, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutar Reference may be made to acids, fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid, oxalic acid, methanesulfonic acid, camphoric acid and the like.

  Among the pharmaceutically acceptable bases, mention may be made of sodium hydroxide, potassium hydroxide, triethylamine, tert-butylamine, etc., without intending any limitation.

Advantageously, R ₁ represents a methyl or cyano group.

In another embodiment of the invention, R ₄ and R ₅ each represent a hydrogen atom.

Preferably R ₃ represents an NH ₂ group.

Alternatively, R ₃ represents a hydrogen atom.

In one embodiment, R ₂ is hydrogen, straight chain or branched (C ₁ -C ₆ ) alkyl group, straight chain or branched (C ₂ -C ₆ ) alkenyl group, straight chain or branched chain ( C ₂ -C ₆ ) alkynyl group,-(C ₁ -C ₆ ) alkylene-O-Cy ₁ group,-(C ₁ -C ₆ ) alkenylene- [O] _n -Cy ₁ group,-(C ₁ -C ₆ ) alkylene-NR-Cy ₁ group,-(C ₁ -C ₆ ) alkylene-S-Cy ₁ group,-(C ₀ -C ₆ ) alkylene-Cy ₂ -Cy ₁ group, or -Cy _2- (C It is understood that the alkyl and alkylene moieties defined herein representing a _2- C ₆ ) alkylene-Cy ₁ group may be straight or branched.

In another embodiment of the invention, R ₂ is Cy ₁ , — (C ₁ -C ₆ ) alkylene-Cy ₁ group, — (C ₀ -C ₆ ) alkylene-Cy ₂ -Cy ₁ group, or —Cy. _It represents a 2- (C ₁ -C ₆ ) alkylene-Cy ₁ group. More preferably, R ₂ is:
A cycloalkyl group,
Or-(C ₁ -C ₆ ) alkylene-cycloalkyl, or-(C ₁ -C ₆ ) alkylene-phenyl group,
Or, -cycloalkylene-phenyl group, or -cycloalkylene- (C ₁ -C ₆ ) alkylene-phenyl group,
Cycloalkyl, cycloalkylene and phenyl groups defined in this way may be optionally substituted according to the definitions already mentioned. Halogen, methoxy and methyl groups are preferred substituents for the aforementioned groups.

In a third embodiment, R ₂ represents a linear or branched (C ₁ -C ₆ ) alkyl group, the alkyl group thus defined may be optionally substituted according to the definition already mentioned Good. -S- halogen and _CH 3 are preferred substituents for an alkyl group.

In a fourth embodiment, R ₂ represents a — (C ₁ -C ₆ ) alkylene-O—Cy ₁ group. More preferably, R ₂ represents a — (C ₁ -C ₆ ) alkylene-O-pyridinyl group, the pyridinyl group thus defined may be optionally substituted according to the definitions already mentioned. Halogen and linear or branched (C ₁ -C ₆ ) polyhaloalkyl groups are preferred substituents for the pyridinyl group.

Preferred compounds according to the invention are the following groups:
4- [2-methyl-3- (3-phenylcyclobutyl) -3H-imidazo [4,5-b] pyridin-5-yl] pyridine-2,6-diamine,
4- [3- (3,3-difluorocyclobutyl) -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl] pyridine-2,6-diamine,
4- (3- {2-[(6-Fluoropyridin-2-yl) oxy] ethyl} -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl) pyridin-2,6- Diamine,
4- {3-[(1R, 2R) -2-benzylcyclopropyl] -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl} pyridin-2,6-diamine,
4- [3- (3-fluorocyclobutyl) -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl] pyridine-2,6-diamine,
4- (3-hexyl-2-methyl-3H-imidazo [4,5-b] pyridin-5-yl) pyridine-2,6-diamine,
4- (3-cyclobutyl-2-methyl-3H-imidazo [4,5-b] pyridin-5-yl) pyridine-2,6-diamine,
4- [3- (2-{[6- (Difluoromethyl) pyridin-2-yl] oxy} ethyl) -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl] pyridine-2 , 6-diamine,
4- [3- (5-Methoxy-2,3-dihydro-1H-inden-2-yl) -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl] pyridin-2,6 A diamine,
4- (3-ethyl-2-methyl-3H-imidazo [4,5-b] pyridin-5-yl) pyridine-2,6-diamine,
4- [2-Methyl-3- (2-{[6- (trifluoromethyl) pyridin-2-yl] oxy} ethyl) -3H-imidazo [4,5-b] pyridin-5-yl] pyridine- 2,6-diamine,
4- {3- [2- (2-methoxycyclohexyl) ethyl] -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl} pyridin-2,6-diamine,
4- (2-methyl-3-pentyl-3H-imidazo [4,5-b] pyridin-5-yl) pyridine-2,6-diamine,
4- (3-cyclohexyl-2-methyl-3H-imidazo [4,5-b] pyridin-5-yl) pyridine-2,6-diamine,
4- {2-methyl-3- [3- (methylsulfanyl) propyl] -3H-imidazo [4,5-b] pyridin-5-yl} pyridin-2,6-diamine,
4- {3-[(1R, 2S) -2-benzylcyclopropyl] -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl} pyridin-2,6-diamine,
4- {2-methyl-3- [2- (2-methylphenyl) ethyl] -3H-imidazo [4,5-b] pyridin-5-yl} pyridine-2,6-diamine,
4- (3- {2-[(6-chloropyridin-2-yl) oxy] ethyl} -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl) pyridine-2,6- Diamine,
4- (3-{(2R) -2-[(6-fluoropyridin-2-yl) oxy] propyl} -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl) pyridine- 2,6-diamine,
4- [2-methyl-3- (2,2,2-trifluoroethyl) -3H-imidazo [4,5-b] pyridin-5-yl] pyridine-2,6-diamine,
3-cyclopentyl-5- (2,6-diaminopyridin-4-yl) -3H-imidazo [4,5-b] pyridine-2-carbonitrile 4- (3-cyclopropyl-2-methyl-3H-imidazo [4,5-b] pyridin-5-yl) pyridine-2,6-diamine,
Included in their enantiomers and diastereoisomers, and their addition salts with pharmaceutically acceptable acids or bases.

（式中、Ａは、ハロゲン原子、又は１〜３個のハロゲン原子によって場合により置換されている直鎖若しくは分枝鎖（Ｃ_１−Ｃ_６）アルキル基を表し、Ｘは、ハロゲン原子を表し、そして、Ｒ_２は、式（Ｉ）に定義されたとおりである）
で示される化合物が使用され、
式（ＩＩ）で示される化合物が、式（ＩＩＩ）：

（式中：
Ｒ_Ｂ１及びＲ_Ｂ２は、水素、直鎖若しくは分枝鎖（Ｃ_１−Ｃ_６）アルキル基を表すか、又はＲ_Ｂ１及びＲ_Ｂ２は、これらを担持する酸素原子と共に、場合によりメチル化されている環を形成し、
Ｒ_Ｂ３は、水素又は基ＮＨ_２を表し、
Ｒ_４及びＲ_５は、式（Ｉ）に定義されたとおりである）
で示される化合物とのカップリングに供されて、式（ＩＶ）：

（式中、Ａは、ハロゲン原子、又は１〜３個のハロゲン原子によって場合により置換されている直鎖若しくは分枝鎖（Ｃ_１−Ｃ_６）アルキル基を表し、Ｒ_Ｂ３は、水素又は基ＮＨ_２を表し、そして、Ｒ_２、Ｒ_４及びＲ_５は、式（Ｉ）に定義されたとおりである）
で示される化合物を得、
式（ＩＶ）で示される化合物が：
Ａがハロゲンを表す場合、Ｅｔ_４ＮＣＮとの反応で、式（Ｉ）（式中、Ｒ_１＝−ＣＮ）で示される化合物を得てもよいか、又は
Ｒ_２が直鎖若しくは分枝鎖ＨＯ−（Ｃ_１−Ｃ_６）アルキレン基を表す場合、芳香族求核置換に供されて、及び／若しくは
酸誘導体の存在下でアシル化に供されて、
式（Ｉ）で示される化合物を得てもよく、
式（Ｉ）で示される化合物が、従来の分離技術により精製されてもよく、それは、所望により、それらの薬学的に許容し得る酸又は塩基との付加塩に変換され、そして、それは、従来の分離技術によりそれらの異性体に場合により分離され、
合成の必要性により、上記プロセスの過程の適切であると考えられる任意の時点で、試薬又は合成の中間体の特定の基（ヒドロキシ、アミノ．．．）を保護し、次いで、脱保護してもよいことが理解される
ことを特徴とする、プロセスに関する。 The present invention is also a process for preparing a compound of formula (I) in which formula (II):

Wherein A represents a halogen atom or a linear or branched (C ₁ -C ₆ ) alkyl group optionally substituted by 1 to 3 halogen atoms, and X represents a halogen atom. And R ₂ is as defined in formula (I))
A compound represented by
A compound of formula (II) is represented by formula (III):

(Where:
R _B1 and R _B2 represent hydrogen, a linear or branched (C ₁ -C ₆ ) alkyl group, or R _B1 and R _B2 are optionally methylated with an oxygen atom carrying them. Form a ring
R _B3 represents hydrogen or a group NH ₂ ;
R ₄ and R ₅ are as defined in formula (I))
For coupling with a compound of formula (IV):

(In the formula, A represents a halogen atom or a linear or branched (C ₁ -C ₆ ) alkyl group optionally substituted with 1 to 3 halogen atoms, and R _B3 represents hydrogen or a group; NH ₂ and R ₂ , R ₄ and R ₅ are as defined in formula (I))
To obtain a compound represented by
The compound of formula (IV) is:
When A represents halogen, reaction with Et ₄ NCN may give a compound of formula (I) (wherein R ₁ = —CN) or R ₂ is linear or branched When representing a HO- (C ₁ -C ₆ ) alkylene group, subjected to aromatic nucleophilic substitution and / or subjected to acylation in the presence of an acid derivative;
You may obtain the compound shown by a formula (I),
The compounds of formula (I) may be purified by conventional separation techniques, which are optionally converted to their addition salts with pharmaceutically acceptable acids or bases, which are conventionally Optionally separated into their isomers by the separation technique of
Depending on the needs of the synthesis, at any point considered appropriate in the course of the above process, certain groups (hydroxy, amino ...) of the reagent or synthesis intermediate are protected and then deprotected. It relates to a process, characterized in that it may be understood that

（式中、Ａ’は、１〜３個のハロゲン原子によって場合により置換されている直鎖又は分枝鎖（Ｃ_１−Ｃ_６）アルキル基を表し、そして、Ｘは、ハロゲン原子を表す）
で示される化合物が使用され、
式（ＩＩ’）で示される化合物が、式（ＩＩＩ）：

（式中：
Ｒ_Ｂ１及びＲ_Ｂ２は、水素、直鎖若しくは分枝鎖（Ｃ_１−Ｃ_６）アルキル基を表すか、又はＲ_Ｂ１及びＲ_Ｂ２は、これらを担持する酸素原子と共に、場合によりメチル化されている環を形成し、
Ｒ_Ｂ３は、水素又は基ＮＨ_２を表し、
Ｒ_４及びＲ_５は、式（Ｉ）に定義されたとおりである）
で示される化合物とのカップリングに供されて、式(ＩＶ’）：

（式中：
Ａ’は、１〜３個のハロゲン原子によって場合により置換されている直鎖又は分枝鎖（Ｃ_１−Ｃ_６）アルキル基を表し、
Ｒ_Ｂ３は、水素又は基ＮＨ_２を表し、
Ｒ_４及びＲ_５は、式（Ｉ）に定義されたとおりである）
で示される化合物を得、
式（ＩＶ’）で示される化合物が：
Ａ）式Ｒ_２−ＮＨ_２（式中、Ｒ_２は、式（Ｉ）に定義されたとおりである）で示される化合物の存在下で求核置換に供されて、式（Ｖ’）：

（式中：
Ａ’は、１〜３個のハロゲン原子によって場合により置換されている直鎖又は分枝鎖（Ｃ_１−Ｃ_６）アルキル基を表し、
Ｒ_Ｂ３は、水素又は基ＮＨ_２を表し、
Ｒ_２、Ｒ_４及びＲ_５は、式（Ｉ）に定義されたとおりである）
で示される化合物を得、
式（Ｖ’）で示される化合物が酸性媒体中、分子内反応（閉環）を受けて、式（Ｉ）で示される化合物を得るか、
Ｂ）又は、式（ＶＩ’）：

（式中：
Ｒは、直鎖若しくは分枝鎖（Ｃ_１−Ｃ_６）アルキル基、場合により置換されているアリール、又は直鎖若しくは分枝鎖ポリハロゲン化（Ｃ_１−Ｃ_６）アルキル基であり、
Ａ’は、１〜３個のハロゲン原子によって場合により置換されている直鎖又は分枝鎖（Ｃ_１−Ｃ_６）アルキル基を表し、
Ｒ_Ｂ３は、水素又は基ＮＨ_２を表し、
Ｒ_４及びＲ_５は、式（Ｉ）に定義されたとおりである）
で示される対応するイミノスルホナート誘導体に変換され、
式（ＶＩ’）で示される化合物が、更に、式Ｒ_２−ＮＨ_２（式中、Ｒ_２は、式（Ｉ）に定義されたとおりである）で示される化合物の存在下で求核置換に供されて、式（ＶＩＩ’）：

（式中：
Ａ’は、１〜３個のハロゲン原子によって場合により置換されている直鎖又は分枝鎖（Ｃ_１−Ｃ_６）アルキル基を表し、
Ｒ_Ｂ３は、水素又は基ＮＨ_２を表し、
Ｒ_２、Ｒ_４及びＲ_５は、式（Ｉ）に定義されたとおりである）
で示される化合物を得、
式（ＶＩＩ’）で示される化合物が分子内有機金属カップリング反応を受けて、式（Ｉ）（式中、Ｒ_１の定義は、Ａ’のうちの１つに限定される）で示される化合物を得るか
のいずれかであり、
式（Ｉ）で示される化合物が、従来の分離技術により精製されてもよく、それは、所望により、それらの薬学的に許容し得る酸又は塩基との付加塩に変換され、そして、それは、従来の分離技術によりそれらの異性体に場合により分離され、
合成の必要性により、上記プロセスの過程の適切であると考えられる任意の時点で、試薬又は合成の中間体の特定の基（ヒドロキシ、アミノ．．．）を保護し、次いで、脱保護してもよいことが理解される
ことを特徴とする、プロセスに関する。 The present invention is also an alternative process for preparing a compound of formula (I), in which formula (II ′):

Wherein A ′ represents a linear or branched (C ₁ -C ₆ ) alkyl group optionally substituted with 1 to 3 halogen atoms, and X represents a halogen atom.
A compound represented by
A compound of formula (II ′) is represented by formula (III):

(Where:
R _B1 and R _B2 represent hydrogen, a linear or branched (C ₁ -C ₆ ) alkyl group, or R _B1 and R _B2 are optionally methylated with an oxygen atom carrying them. Form a ring
R _B3 represents hydrogen or a group NH ₂ ;
R ₄ and R ₅ are as defined in formula (I))
For coupling with a compound of formula (IV ′):

(Where:
A ′ represents a linear or branched (C ₁ -C ₆ ) alkyl group optionally substituted by 1 to 3 halogen atoms,
R _B3 represents hydrogen or a group NH ₂ ;
R ₄ and R ₅ are as defined in formula (I))
To obtain a compound represented by
The compound of formula (IV ′) is:
A) Subjected to nucleophilic substitution in the presence of a compound of formula R ₂ —NH ₂ , wherein R ₂ is as defined in formula (I), formula (V ′):

(Where:
A ′ represents a linear or branched (C ₁ -C ₆ ) alkyl group optionally substituted by 1 to 3 halogen atoms,
R _B3 represents hydrogen or a group NH ₂ ;
R ₂ , R ₄ and R ₅ are as defined in formula (I))
To obtain a compound represented by
The compound of formula (V ′) undergoes an intramolecular reaction (ring closure) in an acidic medium to give a compound of formula (I),
B) or formula (VI ′):

(Where:
R is a linear or branched (C ₁ -C ₆ ) alkyl group, an optionally substituted aryl, or a linear or branched polyhalogenated (C ₁ -C ₆ ) alkyl group;
A ′ represents a linear or branched (C ₁ -C ₆ ) alkyl group optionally substituted by 1 to 3 halogen atoms,
R _B3 represents hydrogen or a group NH ₂ ;
R ₄ and R ₅ are as defined in formula (I))
Converted to the corresponding iminosulfonate derivative represented by
The compound of formula (VI ′) is further nucleophilic substituted in the presence of a compound of formula R ₂ —NH ₂ , wherein R ₂ is as defined in formula (I). In formula (VII ′):

(Where:
A ′ represents a linear or branched (C ₁ -C ₆ ) alkyl group optionally substituted by 1 to 3 halogen atoms,
R _B3 represents hydrogen or a group NH ₂ ;
R ₂ , R ₄ and R ₅ are as defined in formula (I))
To obtain a compound represented by
The compound represented by the formula (VII ′) undergoes an intramolecular organometallic coupling reaction, and is represented by the formula (I) (wherein the definition of R ₁ is limited to one of A ′) One of obtaining a compound,
The compounds of formula (I) may be purified by conventional separation techniques, which are optionally converted to their addition salts with pharmaceutically acceptable acids or bases, which are conventionally Optionally separated into their isomers by the separation technique of
Depending on the needs of the synthesis, at any point considered appropriate in the course of the above process, certain groups (hydroxy, amino ...) of the reagent or synthesis intermediate are protected and then deprotected. It relates to a process, characterized in that it may be understood that

Compounds of formula (II), (II ′), (III), and amine R ₂ —NH ₂ are either commercially available or conventional chemistry described in the literature by those skilled in the art. Which can be obtained using a reaction.

  Pharmacological studies of the compounds of the present invention showed that they are potent DYRK1 / CLK1 inhibitors with higher selectivity for DYRK1 and CLK1 than other kinases such as CDK9.

  More particularly, the compounds according to the invention are useful in the treatment of chemotherapy-resistant or radiation-resistant cancer.

  Among the cancer treatments envisaged, reference may be made to blood cancers (lymphomas and leukemias) and solid tumors (including carcinomas, sarcomas or blastomas), without intending to be limited in any way. More preferably, acute megakaryoblastic leukemia (AMKL), acute lymphoblastic leukemia (ALL), ovarian cancer, pancreatic cancer, gastrointestinal stromal tumor (GIST), osteosarcoma (OS), colorectal carcinoma (CRC) ), Neuroblastoma and glioblastoma.

  In another embodiment, the compounds of the invention are useful in the treatment of Alzheimer's disease, Parkinson's disease and Huntington's disease, and neurodegenerative disorders such as Down's syndrome, mental retardation and movement disorders.

  Alternatively, the compounds of the invention can be used in the treatment and / or prevention of metabolic disorders including diabetes and obesity.

  The invention also relates to a pharmaceutical composition comprising at least one compound of formula (I), in combination with one or more pharmaceutically acceptable excipients.

  Among the pharmaceutical compositions according to the invention, more particularly oral, parenteral, intranasal, trans-cutaneous or trans-cutaneous, rectal, sublingual, intraocular or respiratory administration ( In particular, tablets or dragees, sublingual tablets, sachets, packets, capsules, glossettes, lozenges, suppositories, creams, ointments, skin gels, and drinkable or injectable Reference may be made to those suitable for ampoules.

  Dosage will vary depending on the patient's sex, age and weight, route of administration, therapeutic indication or any relevant treatment nature, and in the range of 0.01 mg to 5 g per 24 hours for one or more administrations. is there.

  Furthermore, the present invention also provides a compound represented by the formula (I), a genotoxic agent, a mitotic toxin, an antimetabolite, a proteasome inhibitor, a kinase inhibitor, a signal transduction pathway inhibitor, a phosphatase inhibitor, apoptosis It relates to combinations with anti-cancer agents selected from inducers and antibodies, and also to pharmaceutical compositions comprising such combinations and their use in the manufacture of medicaments for use in the treatment of cancer.

  The combination of the compound of formula (I) and the anticancer agent may be administered simultaneously or sequentially. The route of administration is preferably the oral route, and the corresponding pharmaceutical composition may allow immediate or delayed release of the active ingredient. Furthermore, the combination of compounds is administered in the form of two separate pharmaceutical compositions, each containing one of the active ingredients, or in the form of a single pharmaceutical composition in which the active ingredients are mixed. Also good.

  The compounds of the invention may also be used in combination with radiation therapy in the treatment of cancer.

List of abbreviations
Abbreviation name Ac acetyl CDI 1,1-carbonyldiimidazole DCM dichloromethane DME 1,2-dimethoxyethane DMF N, N-dimethylformamide DMSO dimethyl sulfoxide eq. Equivalent Et Ethyl HPLC-MS Liquid Chromatography-Mass Spectrometry Me Methyl
ⁿ Bu n-butyl
ⁿ BuPAd ₂ n-butyldiadamantylphosphine Ph phenyl PPh ₃ triphenylphosphine
^t Bu tert-butyl TEA triethylamine TFA trifluoroacetic acid THF tetrahydrofuran

  The following preparations and examples illustrate the invention and do not limit it in any way.

General procedure I

Process A:
1 equivalent of a suitable halide derivative, N- [6- (tert-butoxycarbonylamino) -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2 - pyridyl] carbamic acid tert- butyl (preparation 1) 1.2 equivalent and _K 2 CO ₃ 3 eq, 1,2-dimethoxyethane - water 7: dissolved in 1 (8 mL / mmol). Then 0.05 equivalents of palladium acetate and 0.1 equivalents of ⁿ BuPAd ₂ were added and the mixture was heated at 100 ° C. under nitrogen in a microwave reactor until no further conversion was observed. Celite was added to the reaction mixture and the volatiles were evaporated under reduced pressure. The solid residue, 1% NH 3 as eluent _- was purified via flash chromatography on silica gel using MeOH containing and DCM.

Process B:
The product obtained in Step A was stirred in a mixture of DCM (5 mL / mmol) and TFA (5 mL / mmol) until no further conversion was observed. The volatiles were evaporated under reduced pressure, the solid residue was dissolved in ammonia solution (7N in methanol, 20 mL / mmol) and the volatiles were evaporated again under reduced pressure. The crude product was purified via preparative reverse phase chromatography using 5 mM aqueous NH ₄ HCO ₃ and MeCN as eluents.

General procedure II

Process A:
1.0 equivalent of the appropriate amide ( Preparation 2a , Preparation 2b , Preparation 2c or Preparation 2d ) and 5.0 equivalent of 2,6-lutidine were added to dry DCM (0.10 M solution to Preparation 2) . ). The DCM solution was cooled to 0 ° C. under nitrogen and 5.0 equivalents (1.5 M) of nonafluorobutanesulfonic anhydride in DCM was added dropwise. The reaction mixture was allowed to warm to room temperature over 1 hour, then 5 equivalents of the appropriate amine were added in one portion and the mixture was stirred until no further conversion was observed. The DCM mixture was washed with water, dried over Na ₂ SO ₄ , concentrated under reduced pressure and purified via flash chromatography using dichloromethane and methanolic ammonia as eluent to give the amidine intermediate.

Process B:
One equivalent of the amidine intermediate from Step A was dissolved in 1,2-dimethoxyethane (0.15 M solution). 0.2 equivalents of Pd (OAc) ₂ , 0.4 equivalents of PBuAd ₂ and ₂ equivalents of K ₃ PO ₄ are added and the reaction mixture is 115 ° C. under nitrogen in a microwave reactor until no further conversion is observed. Was stirred at. The reaction mixture was concentrated under reduced pressure and purified via flash chromatography using dichloromethane and methanolic ammonia as eluents to give the appropriate BOC-protected examples.

Process C:
According to general procedure I, step B, starting from the product of step B, the appropriate examples were obtained.

General procedure III

Process A:
Under nitrogen, 3 equivalents of sodium hydride were added to a solution of Preparation 3a or Preparation 3b (1 equivalent) in dry DMF (0.25 M) and the resulting mixture was stirred at 0 ° C. for 15 minutes. After the addition of 2 equivalents of the appropriate aryl halide, the mixture was stirred at 50 ° C. for 5 hours. At this point, if the expected product formation was not observed by HPLC-MS, the reaction temperature was increased to 120 ° C. and stirring was continued until no further conversion was observed. After cooling water was added to the reaction mixture, the aqueous phase was extracted with EtOAc. The combined organic phases are washed with brine, dried over MgSO ₄ anhydride, the solvent is removed under reduced pressure, and the crude product is purified by flash chromatography using DCM and MeOH as eluent to give a BOC-protected. Examples were obtained.

Process B:
According to general procedure I, step B, starting from the product of step A, the appropriate examples were obtained.

General procedure IV

Process A:
N- [6- (tert-butoxycarbonylamino) -4- [3- (2-hydroxyethyl) -2-methyl-imidazo [4,5-b] pyridin-5-yl] -2-pyridyl] carbamic acid 1 equivalent of tert-butyl ( Preparation 3a ), 2 equivalents of the appropriate phenol derivative, 2 equivalents of PPh _{3 and} 2 equivalents of ditertbutyl azodicarboxylate were dissolved in THF (10 mL / mmol Preparation 3a ). The mixture was then stirred at 60 ° C. until no further conversion was observed. Celite was added to the reaction mixture and the volatiles were evaporated under reduced pressure. The solid residue was purified via flash chromatography on silica gel with MeOH containing 1% NH ₃ — and DCM as eluent to give the appropriate BOC-protected example.

Process B:
According to general procedure I, step B, starting from the product of step A, the appropriate examples were obtained.

General procedure V

Process A:
A mixture of 1,6-dibromo-3-nitro-pyridine 1 equivalent, K ₂ CO ₃ 3.2 equivalents and a suitable amine 1.05 equivalents of 1,2-dichloroethane (0.17 M for bromopyridine) was further added. Stir at 50 ° C. until no conversion is observed. Water was added to the mixture and the aqueous phase was separated and extracted three times with DCM. The combined organic layers are dried over MgSO ₄ , the solvent is removed under reduced pressure, and the crude product is purified by flash chromatography using dichloromethane and methanol as eluent to give the appropriate 2-amino-3-nitro-6. -Bromopyridine was obtained.

Process B:
1 equivalent of the appropriate 2-amino-3-nitro-6-bromopyridine, 5 equivalents of Fe powder and 0.2 equivalent of NH ₄ Cl were added with EtOH and water (3: 1, 2) until no further conversion was observed. Stirring at 90 ° C. in a mixture of 0.1 M for amino-3-nitro-6-bromopyridine. The reaction mixture was filtered through celite and the solvent was removed under reduced pressure to give the appropriate 2,3-diamino-6-bromopyridine, which was used without further purification.

Process C:
A mixture of 1 equivalent of the appropriate N ² -substituted 2,3-diamino-6-bromopyridine and 1.5 equivalents of CDI was added to dry THF (2,3-diamino-6-bromo until no further conversion was observed. Stirring in a 0.05M solution of pyridine). The solvent is removed under reduced pressure and the crude product is purified by flash chromatography using dichloromethane and methanol as eluents to give the appropriate 5-bromo-2-oxo-1H-imidazo [4,5-b] pyridine. Obtained.

Process D:
A mixture of 1 equivalent of 3-substituted-5-bromo-2-oxo-1H-imidazo [4,5-b] pyridine and POCl ₃ (5 ml) was stirred at 108 ° C. until no further conversion was observed. POCl ₃ was removed under reduced pressure. Dichloromethane and brine were added, the organic phase was separated and the aqueous phase was extracted twice with dichloromethane. The combined organic layers are dried over MgSO ₄ , the solvent is removed under reduced pressure, and the crude product is purified by flash chromatography using dichloromethane and methanol as eluents to give the appropriate 3-substituted-5-bromo-2. -Chloro-imidazo [4,5-b] pyridine was obtained.

Process E:
Starting from the appropriate 3-substituted-5-bromo-2-chloro-imidazo [4,5-b] pyridine, following the procedure described for Preparation 3a, the appropriate 3-substituted-5- (2,6 -Bis (tert-butoxycarbamoyl) pyridin-4-yl) -2-chloro-imidazo [4,5-b] pyridine was obtained.

Process F:
1 equivalent of the appropriate 3-substituted-5- (2,6-bis (tert-butoxycarbamoyl) pyridin-4-yl) -2-chloro-imidazo [4,5-b] pyridine and tetraethylammonium cyanide. 05 equivalents of the mixture were stirred in DMSO (0.03 M solution in imidazopyridine) until no further conversion was observed. The reaction mixture was poured into water, the solid was filtered off, and the aqueous phase was extracted with chloroform. The organic layers were combined, dried over MgSO ₄ anhydride, and the solvent was removed under reduced pressure. The crude product is purified by flash chromatography using dichloromethane and ethyl acetate as eluent to give the appropriate 3-substituted-5- (2,6-bis (tert-butoxycarbamoyl) pyridin-4-yl) -2. -Cyano-imidazo [4,5-b] pyridine was obtained.

Process G:
According to general procedure I, step B, starting from the product of step F, the appropriate examples were obtained.

General procedure VI

Process A:
1 equivalent of 6-chloro-2-methylamino-3-aminopyridine ( Preparation 4 ) and 2.5 equivalents of the appropriate acetic acid derivative are dissolved in toluene (1 mL / mmol) and the mixture is subjected to further conversion. Stir at 85 ° C. until no longer observed. The volatiles were evaporated under reduced pressure and the solid residue was purified via flash chromatography on silica gel using methanol and DCM as eluent to give 5-chloro-3-methyl-2- (trifluoromethyl ) Imidazo [4,5-b] pyridine was obtained.
¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.39 (d, 1H), 7.57 (d, 1H), 3.95 (s, 3H) or 5-chloro-2- (difluoromethyl) -3-methyl-imidazo [4,5-b] pyridine ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.27 (d, 1H), 7.46 (d, 1H), 7.44 (t, 1H), 3.9 (s, 3H).

Process B:
1 equivalent of the product obtained in Step A , N- [6- (tert-butoxycarbonylamino) -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl ) -2-pyridyl] carbamic acid tert- butyl (preparation 1) 1.3 dissolved in equivalent and _K 3 PO ₄ 2 equivalents of 1,2-dimethoxyethane (6 mL / mmol), then, Pd (PPh ₃ ) ₄ 0.1 equivalent was added and the resulting mixture was heated at 100 ° C. under nitrogen using microwave irradiation until no further conversion was observed. Celite was added to the reaction mixture and the volatiles were evaporated under reduced pressure. The solid residue was purified via flash chromatography on silica gel using MeOH and DCM as eluents to give the BOC-protected example.

Process C:
According to general procedure I, step B, starting from the product of step B, the appropriate examples were obtained.

適切な酸クロリド誘導体の１．０５当量を、４−（３−ブチル−２−メチル−３Ｈ−イミダゾ［４，５−ｂ］ピリジン−５−イル）ピリジン−２，６−ジアミン（実施例１４８） １当量及びトリエチルアミン ３当量のＴＨＦ（１６mL/mmolの実施例１４８）中溶液に−７８℃で滴下して加えた。得られた混合物を室温まで放温し、更なる変換が観察されなくなるまで撹拌した。揮発物を減圧下でエバポレートし、粗生成物を溶離剤として５mM ＮＨ_４ＨＣＯ_３水溶液及びＭｅＣＮを用いる分取逆相クロマトグラフィーを介して精製して、適切な実施例を得た。 General procedure VII

1.05 equivalents of the appropriate acid chloride derivative was added to 4- (3-butyl-2-methyl-3H-imidazo [4,5-b] pyridin-5-yl) pyridin-2,6-diamine ( Example 148). ) 1 equivalent and triethylamine 3 eq. In THF (16 mL / mmol Example 148) was added dropwise at -78 ° C. The resulting mixture was allowed to warm to room temperature and stirred until no further conversion was observed. Volatiles were evaporated under reduced pressure and the crude product was purified via preparative reverse phase chromatography using 5 mM NH ₄ HCO ₃ aqueous solution and MeCN as eluent to give the appropriate examples.

General procedure VIII
Process A:
A mixture of 1 equivalent of 3-acetamino-2-fluoro-6-bromopyridine and 5 equivalents of the appropriate amine in ethanol (2M for amine) was stirred at 50 ° C. until no further conversion was observed. Solvent and excess amine were removed under reduced pressure and the crude 3-acetamino-2-amino-6-bromopyridine derivative was used in the next step without further purification.

Process B:
A solution of the crude 3-acetamino-2-amino-6-bromopyridine derivative in acetic acid (starting 3-acetamino-2-fluoro-6-bromopyridine 1.2 mL / mmol) until no further conversion is observed. Heated at 120 ° C. The solvent is removed under reduced pressure, the residue is dissolved in EtOAc, the organic phase is washed with 10% K ₂ CO ₃ , brine, it is dried over anhydrous MgSO ₄ and evaporated to dryness under reduced pressure. I let you. The crude product was purified by column chromatography using heptane and EtOAc as eluents to give the appropriate 3-substituted 5-bromo-2-methyl-imidazo [4,5-b] pyridine derivative.

適切なアリールハロゲン化物誘導体 １当量の１，２−ジメトキシエタン−水 ７：１（８mL/mmol）中溶液に、４−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）ピリジン−２−アミン １．１当量、Ｋ_３ＰＯ_４３当量、Ｐｄ（ＯＡｃ）_２ ０．０５当量及び^ｎＢｕＰＡｄ_２０．１当量加を加え、混合物を、更なる変換が観察されなくなるまで、アルゴン雰囲気下で９０℃にて撹拌した。混合物をｃｅｌｉｔｅのパッドに通して濾過し、濾液を減圧下で濃縮し、溶離剤として５mM ＮＨ_４ＨＣＯ_３水溶液及びＭｅＣＮを用いる分取逆相クロマトグラフィーを介して精製して、適切な実施例を得た。 General procedure IX

Appropriate aryl halide derivatives 1 equivalent of 1,2-dimethoxyethane-water 7: 1 (8 mL / mmol) in solution in 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane 2-yl) pyridin-2-amine 1.1 equivalents, K ₃ PO ₄ 3 equivalents, Pd (OAc) ₂ 0.05 equivalents and ⁿ BuPAd ₂ 0.1 equivalents were added and the mixture was subjected to further conversion. Stir at 90 ° C. under an argon atmosphere until no longer observed. The mixture was filtered through a pad of celite, the filtrate was concentrated under reduced pressure and purified via preparative reverse phase chromatography using 5 mM NH ₄ HCO ₃ aqueous solution and MeCN as eluent to give suitable examples. Obtained.

General procedure X

Process A:
One equivalent of the appropriate 3-substituted 5-bromo-2-methyl-imidazo [4,5-b] pyridine derivative, 4,4,5,5-tetramethyl-2- (4,4,5,5-tetra Methyl-1,3,2-dioxaborolan-2-yl) -1,3,2-dioxaborolane 2.4 equivalents, Pd (OAc) ₂ 0.1 equivalents, bis (1-adamantyl) -butyl-phosphane 0.2 A mixture of 1 equivalent and ₃ equivalents of K ₃ PO ₄ is dispersed in 1,2-dimethoxyethane (0.25 M solution for the imidazopyridine derivative) and the resulting mixture is placed under a nitrogen atmosphere until no further conversion is observed. And stirred at 90 ° C. The reaction mixture was filtered through celite and the celite was washed with 1,2-dichloroethane. The organic layers are combined, dried over MgSO ₄ , the solvent is removed under reduced pressure, and the crude product is purified by flash chromatography using dichloromethane and methanol as eluent to give the appropriate 3-substituted-2-methyl. -5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) imidazo [4,5-b] pyridine was obtained.

Process B:
1 equivalent of 3-substituted-2-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) imidazo [4,5-b] pyridine, 4-bromo A mixture of 1.05 equivalents of the pyridine derivative, 0.1 equivalents of Pd (OAc) _2, 0.2 equivalents of bis (1-adamantyl) -butyl-phosphane and 4 equivalents of K ₃ PO _{4 was} added to 1,2-dimethoxyethane ( The imidazopyridine derivative was dispersed in a 0.17M solution. The reaction mixture was stirred at 90 ° C. under a nitrogen atmosphere until no further conversion was observed. The reaction mixture was filtered through celite and the celite was washed with 1,2-dichloroethane. The organic layers were combined, dried over MgSO ₄ , the solvent removed under reduced pressure, and the crude product was purified by flash chromatography using dichloromethane and methanol as eluents to give the expected product.

Preparation 1: N- [6- (tert-butoxycarbonylamino) -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2-pyridyl] carbamic acid tert-butyl
109.7 g (283 mmol) of (4-bromo-6-tert-butoxycarbonylamino-pyridin-2-yl) -carbamic acid tert-butyl ester prepared according to J. Org. Chem., 2004 , 69, 543-548, Bis (pinacolato) diboron 107.7 g (424 mmol), Pd (OAc) ₂ 0.29 g (1.27 mmol), 1,1′-bis (diphenylphosphino) ferrocene 0.70 g (1.27 mmol) and KOAc 83. 2 g (848 mmol) was added to previously degassed 1,4-dioxane (1100 mL) and the mixture was stirred at 80 ° C. under an argon atmosphere until no further conversion was observed. The reaction mixture was then filtered; the solid was washed with dioxane. Charcoal (5.5 g) was added to the filtrate and it was stirred at reflux for 2 minutes. The mixture was filtered and washed with warm 1,4-dioxane, and the volatiles were evaporated under reduced pressure. The residue was crystallized from tert-butyl-methyl-ether to give Preparation 1 as a white crystalline solid.
¹ H NMR (500 MHz, CDCl ₃ ) δ: 8.16 (brs, 2H), 7.92 (s, 2H), 1.54 (s, 18H), 1.34 (s, 12H).

Preparation 2a tert-butyl N- [6- (tert-butoxycarbonylamino) -4- [6-chloro-5- (acetylamino) -2-pyridyl] -2-pyridyl] carbamate

Step A: N- (6-Bromo-2-chloro-3-pyridyl) acetamide 61.4-Bromo-2-chloro-pyridin-3-amine 31.4 g (151.3 mmol) was dissolved in glacial acetic acid (200 ml). Acetic anhydride, 15 mL (158.9 mmol) was added dropwise to this solution and the reaction mixture was stirred at room temperature until no further conversion was observed. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and the organic phase was washed with 10% aqueous K ₂ CO ₃ and brine. After drying with Na ₂ SO ₄ , the solvent was removed under reduced pressure to obtain N- (6-bromo-2-chloro-3-pyridyl) acetamide.
HPLC-MS: (M-H) = 247.0; 249.0

Step B: N- [6- (tert-butoxycarbonylamino) -4- [6-chloro-5- (acetylamino) -2-pyridyl] -2-pyridyl] carbamate tert-butyl N- (6-bromo -2-chloro-3-pyridyl) acetamide 13.1 g (52.5 mmol), N- [6- (tert-butoxycarbonylamino) -4- (4,4,5,5-tetramethyl-1,3 2-Dioxaborolan-2-yl) -2-pyridyl] carbamate tert-butyl ( Preparation 1 ) 24.0 g (55.13 mmol) and K ₃ PO ₄ 33.4 g (157.3 mmol) Dissolved in dimethoxyethane-water 4: 1 (250 mL). Then 304 mg (0.26 mmol) of tetrakis (triphenylphosphine) palladium (0) was added and the mixture was heated at 90 ° C. under nitrogen until no further conversion was observed. The mixture was then diluted with water (250 mL) and extracted with EtOAc. The organic layer is dried over Na ₂ SO ₄ , volatiles are removed under reduced pressure, and the residue is recrystallized from EtOAc to give N- [6- (tert-butoxycarbonylamino) -4- [6- Chloro-5- (acetylamino) -2-pyridyl] -2-pyridyl] carbamate tert-butyl was obtained.
¹ H NMR (500 MHz, DMSO-d6) δ: 9.80 (s, 1H), 9.51 (s, 2H), 8.40 (d, 1H), 8.00 (s, 2H), 7.92 (d, 1H), 2.18 ( s, 3H), 1.49 (s, 18H).

Preparation 2b tert-Butyl N- [6- (tert-butoxycarbonylamino) -4- [6-chloro-5- (pentanoylamino) -2-pyridyl] -2-pyridyl] carbamate

Step A: N- (6-Bromo-2-chloro-3-pyridyl) pentanamide 6-bromo-2-chloro-pyridin-3-amine 3.0 g (14.5 mmol) and triethylamine 2.4 mL (17.4 mmol) ) Was dissolved in 60 mL DCM. The solution was cooled to 0 ° C. and 2.1 ml (17.4 mmol) of pentanoyl chloride was added dropwise over 30 minutes. Once the addition was complete, the reaction mixture was allowed to warm to room temperature and it was stirred until no further conversion was observed. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was washed with brine, dried over MgSO ₄ , filtered and concentrated under reduced pressure. The residue was purified via flash chromatography using DCM as eluent to give N- (6-bromo-2-chloro-3-pyridyl) pentanamide as a pale pink solid.
HPLC-MS: (M-H) = 289.0; 291.0

Step B: Step of preparation tert-butyl N- [6- (tert-butoxycarbonylamino) -4- [6-chloro-5- (pentanoylamino) -2-pyridyl] -2-pyridyl] carbamate According to B, starting from N- (6-bromo-2-chloro-3-pyridyl) pentanamide, N- [6- (tert-butoxycarbonylamino) -4- [6-chloro-5- (pentanoyl) Amino) -2-pyridyl] -2-pyridyl] carbamate tert-butyl was obtained.
¹ H NMR (500 MHz, DMSO-d6) δ: 9.70 (s, 1H), 9.45 (s, 2H), 8.37 (d, 1H), 8.00 (s, 2H), 7.91 (d, 1H), 2.47 ( t, 2H), 1.6 (m, 2H), 1.49 (s, 18H), 1.36 (m, 2H), 0.91 (t, 3H).

Preparation 2c tert-butyl N- [6- (tert-butoxycarbonylamino) -4- [6-chloro-5- (propanoylamino) -2-pyridyl] -2-pyridyl] carbamate

Step A: N- (6-Bromo-2-chloro-3-pyridyl) propanamide 6-bromo-2-chloro-pyridin-3-amine 3.0 g (14.5 mmol) and triethylamine 2.4 mL (17.4 mmol) ) Was dissolved in DCM (60 ml). The solution was cooled to 0 ° C. and propanoyl chloride (1.5 ml) was added dropwise over 30 minutes. Once the addition was complete, the reaction mixture was allowed to warm to room temperature and stirred until no further conversion was observed. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was washed with brine, dried over MgSO ₄ , filtered and concentrated under reduced pressure. The residue was purified via flash chromatography using DCM as eluent to give N- (6-bromo-2-chloro-3-pyridyl) propanamide.
HPLC-MS: (M-H) = 261.0; 263.0

Step B: Step of tert-butyl N- [6- (tert-butoxycarbonylamino) -4- [6-chloro-5- (propanoylamino) -2-pyridyl] -2-pyridyl] carbamate preparation 2a According to B, starting from N- (6-bromo-2-chloro-3-pyridyl) propanamide, N- [6- (tert-butoxycarbonylamino) -4- [6-chloro-5- (propanoyl) Amino) -2-pyridyl] -2-pyridyl] carbamate tert-butyl was obtained.
¹ H NMR (500 MHz, DMSO-d6) δ: 9.68 (s, 1H), 9.45 (s, 2H), 8.40 (d, 1H), 8.00 (s, 2H), 7.91 (d, 1H), 2.48 ( q, 2H), 1.49 (s, 18H), 1.11 (t, 3H).

Preparation 2d tert-butyl N- [6- (tert-butoxycarbonylamino) -4- [6-chloro-5- (butanoylamino) -2-pyridyl] -2-pyridyl] carbamate

Step A: N- (6-Bromo-2-chloro-3-pyridyl) butanamide 6-bromo-2-chloro-pyridin-3-amine 3 g (14.46 mmol) and triethylamine 2.4 ml (17.35 mmol, 1. 2 equivalents) was dissolved in DCM (60 ml). The solution was cooled to 0 ° C. and 1.8 ml (17.35 mmol, 1.2 eq) butanoyl chloride was added dropwise over 30 minutes. Once the addition was complete, the reaction mixture was allowed to warm to room temperature and stirred until no further conversion was observed. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was washed with brine, dried over MgSO ₄ , filtered and concentrated under reduced pressure. The residue was purified via flash chromatography using DCM as eluent to give N- (6-bromo-2-chloro-3-pyridyl) butanamide.
HPLC-MS: (M-H) = 275.0; 277.0

Step B: Step of preparation tert-butyl N- [6- (tert-butoxycarbonylamino) -4- [6-chloro-5- (butanoylamino) -2-pyridyl] -2-pyridyl] carbamate According to B, starting from N- (6-bromo-2-chloro-3-pyridyl) butanamide, N- [6- (tert-butoxycarbonylamino) -4- [6-chloro-5- (butiroyl) ) Amino) -2-pyridyl] -2-pyridyl] carbamate tert-butyl was obtained.
¹ H NMR (500 MHz, DMSO-d6) δ: 9.70 (s, 1H), 9.46 (s, 2H), 8.37 (d, 1H), 8.00 (s, 2H), 7.91 (d, 1H), 2.45 ( t, 2H), 1.64 (m, 2H), 1.49 (s, 18H), 0.95 (t, 3H).

Preparation 3a N- [6- (tert-butoxycarbonylamino) -4- [3- (2-hydroxyethyl) -2-methyl-imidazo [4,5-b] pyridin-5-yl] -2-pyridyl ] Tert-butyl carbamate 5-chloro-3- (2-hydroxyethyl) -2-methyl-imidazo [4,5-b] pyridine 1 equivalent, N- [6- (tert-butoxycarbonylamino) -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2-pyridyl] carbamate tert-butyl ( preparation 1 ) 1.1 equivalents, Pd (OAc) ₂ 0 .1 equivalent, 0.2 equivalent of PBuAd ₂ and 3.0 equivalent of K ₂ CO ₃ were suspended in DME (0.2 M) and the mixture was suspended in a microwave reactor until no further conversion was observed. Stir at 100 ° C under nitrogen . Volatiles were removed under reduced pressure and the crude product was purified via flash chromatography using dichloromethane and methanolic ammonia as eluent to give N- [6- (tert-butoxycarbonylamino) -4- [3. -(2-Hydroxyethyl) -2-methyl-imidazo [4,5-b] pyridin-5-yl] -2-pyridyl] carbamate tert-butyl was obtained as a white solid.
¹ H NMR (400 MHz, DMSO-d6) δ: 9.34 (s, 2H), 8.03 (d, 1H), 8.02 (s, 2H), 7.68 (d, 1H), 4.97 (t, 1H), 4.34 ( t, 2H), 3.81 (q, 2H), 2.63 (s, 3H), 1.49 (s, 18H).

Preparation 3b N- [6- (tert-butoxycarbonylamino) -4- [3- (2-hydroxypropyl) -2-methyl-imidazo [4,5-b] pyridin-5-yl] -2-pyridyl ] Tert-butyl carbamate

Step A: 3-Amino-2-fluoro-6-bromopyridine 1 equivalent of 3-amino-2-fluoropyridine is dissolved in DCM (0.6 M solution), 1.05 equivalent of N-bromosuccinimide is added, and The reaction mixture was stirred at room temperature until no further conversion was observed. Water was added and the organic phase was separated, dried over anhydrous MgSO ₄ and concentrated under reduced pressure to give 3-amino-2-fluoro-6-bromopyridine.
¹ H NMR (400 MHz, DMSO-d6) δ: 7.22 (dd, 1H), 7.11 (dd, 1H), 5.62 (brs, 2H).

Step B: 3-Acetamino-2-fluoro-6-bromopyridine 3-amino-2-fluoro-6-bromopyridine To a solution of 1 equivalent of acetic acid (0.9 M), 1.05 equivalent of acetic anhydride was added and the reaction The mixture was stirred at room temperature until no further conversion was observed. The solvent was removed under reduced pressure and the crude product was dissolved in DCM and washed with 10% K ₂ CO ₃ . The organic layer was dried over MgSO ₄ anhydride and concentrated under reduced pressure to give 3-acetamino-2-fluoro-6-bromopyridine.
¹ H NMR (400 MHz, DMSO-d6) δ: 10.03 (brs, 1H), 8.42 (dd, 1H), 7.56 (d, 1H), 2.11 (s, 3H).

Step C: 3-acetamino-2- (2-hydroxypropylamino) -6-bromopyridine 3-acetamino-2-fluoro-6-bromopyridine 1 equivalent, 1-aminopropan-2-ol 2.2 equivalents and triethylamine A mixture of (fluoropyridine 0.27 mL / mmol) was stirred at 60 ° C. until no further conversion was observed. Solvent and excess amine were removed under reduced pressure and crude 3-acetamino-2- (2-hydroxypropylamino) -6-bromopyridine was used in the next step without purification.
MS: (M + H) ⁺ = 288.2

Step D: 5-Bromo-3- (2-hydroxypropyl) -2-methyl-imidazo [4,5-b] pyridine 3-acetamino-2- (2-hydroxypropylamino) -6-bromopyridine 1 equivalent of A solution in acetic acid (crude amide 13.6 mL / g) was heated at 130 ° C. until no further conversion was observed. The solvent is removed under reduced pressure and the residue is dissolved in methanol: water (5: 1, 7 mL / g residue) containing LiOH * H ₂ O (residue 0.27 g / g) and the mixture is Stir at temperature for 2 hours and pour into water. The precipitate was filtered off, washed with water and dried to give 5-bromo-3- (2-hydroxypropyl) -2-methyl-imidazo [4,5-b] pyridine.
¹ H NMR (400 MHz, DMSO-d6) δ: 7.87 (d, 1H), 7.36 (d, 1H), 4.97 (d, 1H), 4.19-3.94 (m, 3H), 2.57 (s, 3H), 1.21 (d, 3H).

Process E:
5-bromo-3- (2-hydroxypropyl) -2-methyl-imidazo [4,5-b] pyridine 1 equivalent, N- [6- (tert-butoxycarbonylamino) -4- (4,4,5) , 5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2-pyridyl] carbamate tert-butyl ( preparation 1 ) 1.0 equivalent, tetrakis (triphenylphosphine) palladium (0) 05 equivalents and ₃ equivalents of K ₃ PO ₄ are suspended in DME (5 mL / mmol for bromo compound) and the mixture is at 100 ° C. under nitrogen in a microwave reactor until no further conversion is observed. Stir. Volatiles were removed under reduced pressure and the crude product was purified via flash chromatography using dichloromethane and methanolic ammonia as eluent to give N- [6- (tert-butoxycarbonylamino) -4- [3. -(2-Hydroxypropyl) -2-methyl-imidazo [4,5-b] pyridin-5-yl] -2-pyridyl] carbamate tert-butyl was obtained as a white solid.
¹ H NMR (500 MHz, DMSO-d6) δ: 9.42 (s, 2H), 8.10 (s, 2H), 8.03 (d, 1H), 7.70 (d, 1H), 5.03 (d, 1H), 4.28 ( dd, 1H), 4.18 (m, 1H), 4.10 (dd, 1H), 2.64 (s, 3H), 1.50 (s, 18H), 1.19 (d, 3H).

Preparation 4 6-Chloro -N ² - methyl - pyridine-2,3-diamine

Step A: 6-Chloro-N-methyl-3-nitro-pyridin-2-amine 2,6-dichloro-3-nitro-pyridine 3.86 g (20 mmol) was dissolved in DCM (80 ml) and K ₂ CO ₃ 6.9 g (50 mmol, 2.5 eq) was added and the reaction mixture was cooled to −20 ° C. At this temperature 3.1 ml of methylamine (33% solution in ethanol, 28.6 mmol, 1.43 eq) are added dropwise, then the cooling is stopped and the reaction mixture is allowed to warm to ambient temperature. It was stirred until no further conversion was observed. The reaction mixture is filtered, the filtrate is washed with water, the organic layer is dried over MgSO ₄ and then concentrated under reduced pressure to give 6-chloro-N-methyl-3-nitro-pyridin-2-amine. Obtained as a solid.
¹ H NMR (500 MHz, DMSO-d6) δ: 8.72 (d, 1H), 8.42 (d, 1H), 6.77 (d, 1H), 3.08 (d, 3H).

Step B: 6-chloro-2-methylamino-3-aminopyridine 6-chloro-N-methyl-3-nitro-pyridin-2-amine 3.0 g (16 mmol) is dissolved in a mixture of 30 ml ethanol and 15 ml water. Next, 4.47 g (80 mmol, 5 equivalents) of iron powder was added. To this mixture, 1.2 ml of glacial acetic acid was added dropwise and then the reaction mixture was refluxed until no further conversion was observed. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified via flash chromatography using DCM as eluent to give 6-chloro-2-methylamino-3-aminopyridine.
MS (M + H) = 158.2

Preparation 5 4- (3-Butyl-2-methyl-imidazo [4,5-b] pyridin-5-yl) -N ² -triphenylmethyl-pyridine-2,6-diamine triethylamine 8.35 mL (6. 07 g, 60.0 mmol) and 8.36 g (30.0 mmol) of triphenylmethyl chloride were added to 4- (3-butyl-2-methyl-3H-imidazo [4,5-b] pyridin-5-yl) pyridine- 2,6-diamine ( Example 148 ) To a stirred solution of 2.96 g (10.0 mmol) in THF (100 mL) at room temperature was added and the mixture was stirred until no further conversion was observed. Volatiles were evaporated under reduced pressure and the crude product was purified via reverse phase flash chromatography using water and MeCN as eluent to give 4- (3-butyl-2-methyl-imidazo [4,5- b] ^{pyridin-5-yl)} -N 2, ^{N 6} - di (triphenylmethyl) - pyridine-2,6-diamine as an intermediate. This intermediate is dissolved in methanol (400 mL), TFA (20 mL) is added at room temperature, and the mixture is added until the total amount of bis-triphenylmethylated intermediate is converted to the desired product. Stir at room temperature. Next, 16.0 g (202.4 mmol) of NH ₄ HCO ₃ was added with stirring and the precipitate formed was removed by filtration to give the crude product, which was recrystallized from methanol to give 4- (3-butyl-2-methyl - imidazo [4,5-b] pyridin-5-yl) -N ² - to give pyridine-2,6-diamine (preparation 5) - triphenylmethyl.
¹ H NMR (500 MHz, CDCl ₃ ) δ: 7.84 (d, 1H), 7.42-7.35 (m, 6H), 7.33-7.25 (m, 6H), 7.23-7.16 (m, 3H), 7.20 (d, 1H), 6.33 (s, 1H), 6.26 (brs, 1H), 6.03 (s, 1H), 5.45 (brs, 2H), 4.12 (t, 2H), 2.58 (s, 3H), 1.64 (m, 2H ), 1.16 (m, 2H), 0.85 (t, 3H).

一般手順ＶＩＩＩに従い、適切なアミン誘導体としてブチルアミンを用いて、５−ブロモ−３−ブチル−２−メチル−イミダゾ［４，５−ｂ］ピリジンを得た。
¹H NMR (500 MHz, DMSO-d6) δ：7.89 (d, 1H), 7.38(d, 1H), 4.18 (t, 2H), 2.58 (s, 3H), 1.71 (quint, 2H), 1.38-1.22 (m, 2H), 0.91 (t, 3H)。 Preparation 6a 5-Bromo-3-butyl-2-methyl-imidazo [4,5-b] pyridine

Following general procedure VIII, using 5-butyl-3-butyl-2-methyl-imidazo [4,5-b] pyridine with butylamine as the appropriate amine derivative.
¹ H NMR (500 MHz, DMSO-d6) δ: 7.89 (d, 1H), 7.38 (d, 1H), 4.18 (t, 2H), 2.58 (s, 3H), 1.71 (quint, 2H), 1.38- 1.22 (m, 2H), 0.91 (t, 3H).

Preparation 6b 5-Bromo-3- (2-cyclohexylethyl) -2-methyl-imidazo [4,5-b] pyridine According to general procedure VIII using (2-aminoethyl) -cyclohexane as the appropriate amine derivative 5-bromo-3- (2-cyclohexylethyl) -2-methyl-imidazo [4,5-b] pyridine was obtained.
¹ H NMR (500 MHz, DMSO-d6) δ: 7.88 (d, 1H), 7.38 (d, 1H), 4.19 (t, 2H), 2.57 (s, 3H), 1.79 (d, 2H), 1.66 ( d, 2H), 1.62-1.57 (m, 1H), 1.59 (q, 2H), 1.29-1.08 (m, 4H), 0.94 (q, 2H).

Preparation 6c 5-Bromo-3- (cyclopropylmethyl) -2-methyl-imidazo [4,5-b] pyridine According to General Procedure VIII, using cyclopropyl-methylamine as the appropriate amine derivative, 5-bromo -3- (Cyclopropylmethyl) -2-methyl-imidazo [4,5-b] pyridine was obtained.
¹ H NMR (400 MHz, DMSO-d6) δ: 7.77 (d, 1H), 7.31 (d, 1H), 4.10 (d, 2H), 2.66 (s, 3H), m1.33-1.19 (m, 1H ), 0.64-0.43 (m, 4H).

Preparation 6d 5-Bromo-3-but-3-enyl-2-methyl-imidazo [4,5-b] pyridine According to General Procedure VIII, using 1-amino-3-butene as the appropriate amine derivative, 5 -Bromo-3-but-3-enyl-2-methyl-imidazo [4,5-b] pyridine was obtained.
¹ H NMR (500 MHz, DMSO-d6) δ: 7.88 (d, 1H), 7.38 (d, 1H), 5.86-5.71 (m, 1H), 5.01-4.94 (m, 2H), 4.26 (t, 2H ), 2.57 (s, 3H), 2.52 (q, 2H).

Preparation 6e 5-Bromo-3- (3,3-difluorocyclobutyl) -2-methyl-imidazo [4,5-b] pyridine 3,3-Difluoro-cyclobutanamine as a suitable amine derivative according to General Procedure VIII Was used to give 5-bromo-3- (3,3-difluorocyclobutyl) -2-methyl-imidazo [4,5-b] pyridine.
¹ H NMR (500 MHz, DMSO-d6) δ: 7.91 (d, 1H), 7.42 (d, 1H), 5.05-4.92 (m, 1H), 3.88-3.69 (m, 2H), 3.22-3.09 (m , 2H), 2.60 (s, 3H).

Preparation 6f 5-Bromo-3-cyclopropyl-2-methyl-imidazo [4,5-b] pyridine According to general procedure VIII, using cyclopropylamine as the appropriate amine derivative, 5-bromo-3-cyclopropyl 2-Methyl-imidazo [4,5-b] pyridine was obtained.
¹ H NMR (500 MHz, DMSO-d6) δ: 7.86 (d, 1H), 7.37 (d, 1H), 3.33-3.28 (m, 1H), 2.60 (s, 3H), 1.18-1.11 (m, 4H ).

Example 1 4- (3-Cyclopentyl-2-methyl-3H-imidazo [4,5-b] pyridin-5-yl) pyridine-2,6-diamine According to general procedure I, 6-chloro as the appropriate halide Example 1 was obtained starting from -3-cyclopentyl-2-methyl-imidazo [4,5-b] pyridine. HRMS (TOF, ESI) m / z: Calculated value for C ₁₇ H ₂₀ N ₆ 308.1749, found value: 309.1821 [M + H] ⁺ .

Example 2 4- (2-Methyl-3-propyl-3H-imidazo [4,5-b] pyridin-5-yl) pyridin-2,6-diamine According to General Procedure I, 3-propyl as the appropriate halide Example 2 was obtained starting from -6-chloro-2-methyl-imidazo [4,5-b] pyridine. _{HRMS (TOF, ESI) m /} z: Calculated for _{C 15 H} 18 _{N 6} 282.1593, ^{Found: 283.1662 [M + H] +} .

Example 3 2- [5- (2,6-Diaminopyridin-4-yl) -2-methyl-3H-imidazo [4,5-b] pyridin-3-yl] ethanol According to General Procedure I, the appropriate halogen Example 3 was obtained starting from 6-chloro-3- (2-hydroxyethyl) -2-methyl-imidazo [4,5-b] pyridine as the compound. _{HRMS (TOF, ESI) m /} z: C 14 H 16 N 6 O Calculated 284.1386, ^{Found: 285.1473 [M + H] +} .

Example 4 4- (2,3-Dimethyl-3H-imidazo [4,5-b] pyridin-5-yl) pyridin-2,6-diamine According to general procedure I, 6-chloro-2 as the appropriate halide Example 4 was obtained starting from 1,3-dimethyl-imidazo [4,5-b] pyridine. HRMS (TOF, ESI) m / z: Calculated value for C ₁₃ H ₁₄ N ₆ 2544.1280, found value: 2555.1361 [M + H] ⁺ .

Example 5 4- [2-Methyl-3- (pyridin-4-ylmethyl) -3H-imidazo [4,5-b] pyridin-5-yl] pyridin-2,6-diamine According to general procedure I Example 5 was obtained starting from 6-chloro-3- (4-pyridylmethyl) -2-methyl-imidazo [4,5-b] pyridine as the halide. HRMS (TOF, ESI) m / z: Calculated value for C ₁₈ H ₁₇ N ₇ 331.1545, found value: 332.1623 [M + H] ⁺ .

Example 6 4- [2-Methyl-3- (pyridin-2-ylmethyl) -3H-imidazo [4,5-b] pyridin-5-yl] pyridin-2,6-diamine According to general procedure I Example 6 was obtained starting from 6-chloro-3- (2-pyridylmethyl) -2-methyl-imidazo [4,5-b] pyridine as the halide. HRMS (TOF, ESI) m / z: Calculated value for C ₁₈ H ₁₇ N ₇ 331.1545, found value: 332.1625 [M + H] ⁺ .

Example 7 4- [2-Methyl-3- (pyridin-3-ylmethyl) -3H-imidazo [4,5-b] pyridin-5-yl] pyridin-2,6-diamine According to general procedure I Example 7 was obtained starting from 6-chloro-3- (3-pyridylmethyl) -2-methyl-imidazo [4,5-b] pyridine as the halide. HRMS (TOF, ESI) m / z: Calculated value for C ₁₈ H ₁₇ N ₇ 331.1545, found value: 332.1625 [M + H] ⁺ .

Example 8 4- (3-Benzyl-2-methyl-3H-imidazo [4,5-b] pyridin-5-yl) pyridin-2,6-diamine According to general procedure I, 3-benzyl as the appropriate halide Example 8 was obtained starting from -6-chloro-2-methyl-imidazo [4,5-b] pyridine. HRMS (TOF, ESI) m / z: Calculated value for C ₁₉ H ₁₈ N ₆ 330.1593, found value: 331.1673 [M + H] ⁺ .

Example 9 4- (3-Cyclopropyl-2-methyl-3H-imidazo [4,5-b] pyridin-5-yl) pyridin-2,6-diamine Following general procedure II, starting from preparation 2a Example 9 was obtained using cyclopropylamine as the appropriate amine. HRMS (TOF, ESI) m / z: Calculated value for C ₁₅ H ₁₆ N ₆ 280.1436, found value: 281.1518 [M + H] ⁺ .

Example 10 4- [3- (4-Fluorobenzyl) -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl] pyridin-2,6-diamine Following general procedure II, preparation 2a Example 10 was obtained starting from and using 4-fluorobenzylamine as the appropriate amine. HRMS (TOF, ESI) m / z: Calculated value for C ₁₉ H ₁₇ N ₆ F 348.1499, found value: 3415.1565 [M + H] ⁺ .

Example 11 4- [3- (Cyclopropylmethyl) -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl] pyridin-2,6-diamine Following general procedure II, from Preparation 2a Starting, Example 11 was obtained using cyclopropylmethylamine as the appropriate amine. HRMS (TOF, ESI) m / z: Calculated value for C ₁₆ H ₁₈ N ₆ 294.1593, found value: 295.1665 [M + H] ⁺ .

Example 12 4- [3- (2,3-Dihydro-1H-inden-2-yl) -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl] pyridin-2,6- Diamine Example 12 was obtained according to General Procedure II, starting from Preparation 2a, using 2,3-dihydro-1H-inden-2-amine as the appropriate amine. HRMS (TOF, ESI) m / z: Calculated value for C ₂₁ H ₂₀ N ₆ 356.1749, found value: 357.1822 [M + H] ⁺ .

Example 13 1- {3- [5- (2,6-Diaminopyridin-4-yl) -2-methyl-3H-imidazo [4,5-b] pyridin-3-yl] propyl} pyrrolidine-2- On Example 13 was obtained according to General Procedure II, starting from Preparation 2a, using 1- (3-aminopropyl) pyrrolidin-2-one as the appropriate amine. HRMS (TOF, ESI) m / z: Calculated for C ₁₉ H ₂₃ N ₇ O 365. 1964, found: 366.2035 [M + H] ⁺ .

Example 14 4- [3- (But-3-en-1-yl) -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl] pyridin-2,6-diamine General procedure II Example 14 was obtained starting from preparation 2a using 4-amino-1-butene as the appropriate amine. _{HRMS (TOF, ESI) m /} z: Calculated for _{C 16 H} 18 _{N 6} 294.1593, ^{Found: 295.1672 [M + H] +} .

Example 15 4- [3- (2-Cyclohexylethyl) -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl] pyridin-2,6-diamine Following general procedure II, preparation 2a Starting from, Example 15 was obtained using (2-aminoethyl) -cyclohexane as the appropriate amine. HRMS (TOF, ESI) m / z: Calculated value for C ₂₀ H ₂₆ N ₆ 350.2219, found value: 351.2298 [M + H] ⁺ .

Example 16 4- [2-Methyl-3-[(1S, 2S, 3S, 5R) -2,6,6-trimethylbicyclo [3.1.1] hept-3-yl] -3H-imidazo [4 , 5-b] pyridin-5-yl] pyridin-2,6-diamine Starting from Preparation 2a according to General Procedure II as (1S, 2S, 3S, 5R) -2,6,6 Example 16 was obtained using trimethylbicyclo [3.1.1] heptane-3-amine. HRMS (TOF, ESI) m / z: Calculated value for C ₂₂ H ₂₈ N ₆ 376.2375, found value: 377.2456 [M + H] ⁺ .

Example 17 4- [3- (2-Cyclopropylethyl) -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl] pyridin-2,6-diamine Preparation according to general procedure II Starting from 2a, Example 17 was obtained using 2-cyclopropylethanamine as the appropriate amine. HRMS (TOF, ESI) m / z: Calculated value for C ₁₇ H ₂₀ N ₆ 308.1749, found value: 309.1828 [M + H] ⁺ .

Example 18 4- [3- (2-Ethylbutyl) -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl] pyridin-2,6-diamine Following general procedure II, from Preparation 2a Starting, Example 18 was obtained using 2-ethylbutan-1-amine as the appropriate amine. _{HRMS (TOF, ESI) m /} z: Calculated for _{C 18 H} 24 _{N 6} 324.2062, ^{Found: 325.2139 [M + H] +} .

Example 19 4- {3- [2- (Furan-2-yl) ethyl] -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl} pyridin-2,6-diamine General procedure Example 19 was obtained according to II, starting from Preparation 2a, using 2- (2-furyl) ethanamine as the appropriate amine. HRMS (TOF, ESI) m / z: Calculated value for C ₁₈ H ₁₈ N ₆ O 334.1542, found value: 335.1618 [M + H] ⁺ .

Example 20 4- [2-Methyl-3- (thiophen-2-ylmethyl) -3H-imidazo [4,5-b] pyridin-5-yl] pyridin-2,6-diamine Prepared according to general procedure II Example 20 was obtained starting from 2a using 2-thienylmethanamine as the appropriate amine. HRMS (TOF, ESI) m / z: Calculated value for C ₁₇ H ₁₆ N ₆ S 336.1157, found value: 317.1224 [M + H] ⁺ .

Example 21 4- {2-Methyl-3- [2- (1-phenyl-1H-pyrazol-4-yl) ethyl] -3H-imidazo [4,5-b] pyridin-5-yl} pyridine-2 , 6-diamine Example 21 was obtained according to general procedure II, starting from preparation 2a, using 2- (1-phenylpyrazol-4-yl) ethanamine as the appropriate amine. HRMS (TOF, ESI) m / z: Calculated value for C ₂₃ H ₂₂ N ₈ 410.1967, found value: 4112.238 [M + H] ⁺ .

Example 22 4- {2-Methyl-3-tricyclo [3.3.1.1 ^3,7 ] dec-1-ylmethyl-3H-imidazo [4,5-b] pyridin-5-yl} pyridine-2 , 6-diamine Following Example II, starting from Preparation 2a, using Example 1 with 1-adamantylmethanamine as the appropriate amine. HRMS (TOF, ESI) m / z: Calculated value for C ₂₃ H ₂₈ N ₆ 3888.2375, found value: 389.2542 [M + H] ⁺ .

Example 23 4- (3-Cyclobutyl-2-methyl-3H-imidazo [4,5-b] pyridin-5-yl) pyridin-2,6-diamine According to general procedure II, starting from preparation 2a, Example 23 was obtained using cyclobutylamine as the appropriate amine. HRMS (TOF, ESI) m / z: Calculated value for C ₁₆ H ₁₈ N ₆ 294.1593, found value: 295.1665 [M + H] ⁺ .

Example 24 N- (4- {2- [5- (2,6-diaminopyridin-4-yl) -2-methyl-3H-imidazo [4,5-b] pyridin-3-yl] ethyl} phenyl ) Acetamide Example 24 was obtained according to General Procedure II, starting from Preparation 2a, using N- [4- (2-aminoethyl) phenyl] acetamide as the appropriate amine. HRMS (TOF, ESI) m / z: Calculated value for C ₂₂ H ₂₃ N ₇ O 401.1964, found value: 402.2039 [M + H] ⁺ .

Example 25 4- (3-tert-Butyl-2-methyl-3H-imidazo [4,5-b] pyridin-5-yl) pyridin-2,6-diamine Following general procedure II, starting from preparation 2a. Example 25 was obtained using tert-butylamine as the appropriate amine. _{HRMS (TOF, ESI) m /} z: Calculated for _{C 16 H} 20 _{N 6} 296.1479, _{Found: 240.1125 [M + H-C} 4 H 8] +. Fragment ion formula: C ₁₂ H ₁₂ N ₆ molecular ions were not detected by extensive fragmentation.

Example 26 4- {2-Methyl-3- [2- (thiophen-2-yl) ethyl] -3H-imidazo [4,5-b] pyridin-5-yl} pyridin-2,6-diamine General procedure Example 26 was obtained according to II, starting from Preparation 2a, using 2-thienylethanamine as the appropriate amine. HRMS (TOF, ESI) m / z: Calculated value for C ₁₈ H ₁₈ N ₆ S 350.1314, found value: 351.1385 [M + H] ⁺ .

Example 27 4- {2-Methyl-3- [2- (naphthalen-1-yloxy) ethyl] -3H-imidazo [4,5-b] pyridin-5-yl} pyridin-2,6-diamine General procedure Example 27 was obtained according to II, starting from Preparation 2a, using 2- (naphthalen-1-yloxy) ethanamine as the appropriate amine. HRMS (TOF, ESI) m / z: Calculated for C ₂₄ H ₂₂ N ₆ O 410.1855, found: 411.1923 [M + H] ⁺ .

Example 28 4- [2-Methyl-3- (2,2,2-trifluoroethyl) -3H-imidazo [4,5-b] pyridin-5-yl] pyridin-2,6-diamine General procedure II Example 28 was obtained starting from Preparation 2a using 2,2,2-trifluoroethylamine as the appropriate amine. HRMS (TOF, ESI) m / z: Calculated value for C ₁₄ H ₁₃ N ₆ F ₃ 322.1154, found value: 323.1238 [M + H] ⁺ .

Example 29 4- {2-Methyl-3- [2- (thiophen-3-yl) ethyl] -3H-imidazo [4,5-b] pyridin-5-yl} pyridin-2,6-diamine General procedure Example 29 was obtained according to II, starting from Preparation 2a, using 3-thienylethanamine as the appropriate amine. HRMS (TOF, ESI) m / z: Calculated value for C ₁₈ H ₁₈ N ₆ S 350.1314, found value: 351.1379 [M + H] ⁺ .

Example 30 4- [3- (2,2-Dimethylpropyl) -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl] pyridin-2,6-diamine Prepared according to general procedure II Example 30 was obtained starting from product 2a using 2,2-dimethylpropan-1-amine as the appropriate amine. HRMS (TOF, ESI) m / z: Calculated value for C ₁₇ H ₂₂ N ₆ 310.1906, found value: 311.2010 [M + H] ⁺ .

Example 31 4- [2-Methyl-3- (2-methylpropyl) -3H-imidazo [4,5-b] pyridin-5-yl] pyridin-2,6-diamine Following general procedure II, preparation 2a Starting from, Example 31 was obtained using 2-methylpropan-1-amine as the appropriate amine. HRMS (TOF, ESI) m / z: Calculated value of C ₁₆ H ₂₀ N ₆ 296.1749, measured value: 297.1824 [M + H] ⁺

Example 32 4- {2-Methyl-3-[(1R) -1- (2-methylpyridin-4-yl) ethyl] -3H-imidazo [4,5-b] pyridin-5-yl} pyridine- 2,6-diamine Example 32 was obtained according to general procedure II, starting from preparation 2a, using (1R) -1- (2-methyl-4-pyridyl) ethanamine as the appropriate amine. HRMS (IT-TOF, ESI) m / z: Calculated value of C ₂₀ H ₂₁ N ₇ 359.1858, measured value: 360.1934 [M + H] ⁺

Example 33 4- [3- (Butan-2-yl) -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl] pyridine-2,6-diamine Prepared according to general procedure II Starting from 2a, Example 33 was obtained using butan-2-amine as the appropriate amine. HRMS (IT-TOF, ESI) m / z: Calculated value of C ₁₆ H ₂₀ N ₆ 296.1749, measured value: 297.1826 [M + H] ⁺

Example 34 4- [2-Methyl-3- (2-methylbutyl) -3H-imidazo [4,5-b] pyridin-5-yl] pyridin-2,6-diamine Following general procedure II, from Preparation 2a Starting, Example 34 was obtained using 2-methylbutan-1-amine as the appropriate amine. HRMS (IT-TOF, ESI) m / z: Calculated value of C ₁₇ H ₂₂ N ₆ 310.1906, measured value: 311.1983 [M + H] ⁺

Example 35 Ethyl 4- [5- (2,6-diaminopyridin-4-yl) -2-methyl-3H-imidazo [4,5-b] pyridin-3-yl] piperidine-1-carboxylate General procedure Example 35 was obtained according to II, starting from Preparation 2a, using ethyl 4-aminopiperidine-1-carboxylate as the appropriate amine. HRMS (TOF, ESI) m / z: Calculated value of C ₂₀ H ₂₅ N ₇ O ₂ 395.2070, measured value: 396.2152 [M + H] ⁺

Example 36 4- [2-Methyl-3- (5,6,7,8-tetrahydroquinolin-5-yl) -3H-imidazo [4,5-b] pyridin-5-yl] pyridine-2,6 -Diamine Example 36 was obtained according to general procedure II, starting from preparation 2a, using 5,6,7,8-tetrahydroquinolin-5-amine as the appropriate amine. HRMS (IT-TOF, ESI) m / z: Calculated value of C ₂₁ H ₂₁ N ₇ 371.1858, measured value: 372.939 [M + H] ⁺

Example 37 3- [5- (2,6-Diaminopyridin-4-yl) -2-methyl-3H-imidazo [4,5-b] pyridin-3-yl] propane-1,2-diol General procedure Example 37 was obtained according to II, starting from Preparation 2a, using 3-aminopropane-1,2-diol as the appropriate amine. HRMS (IT-TOF, ESI) m / z: Calculated value of C ₁₅ H ₁₈ N ₆ O ₂ 314.1491, measured value: 315.1559 [M + H] ⁺

Example 38 1- {4- [5- (2,6-diaminopyridin-4-yl) -2-methyl-3H-imidazo [4,5-b] pyridin-3-yl] piperidin-1-yl} 2-Methylpropan-1-one Following general procedure II and starting from Preparation 2a with 1- (4-amino-1-piperidyl) -2-methyl-propan-1-one as the appropriate amine Example 38 was obtained. HRMS (IT-TOF, ESI) m / z: Calculated value of C ₂₁ H ₂₇ N ₇ O 393.2277, measured value: 394.2356 [M + H] ⁺

Example 39 4- [3- (4-Chloro-2-methoxybenzyl) -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl] pyridin-2,6-diamine According to general procedure II Starting from Preparation 2a, Example 39 was obtained using (4-chloro-2-methoxy-phenyl) methanamine as the appropriate amine. HRMS (IT-TOF, ESI) m / z: Calculated value of C ₂₀ H ₁₉ N ₆ OCl 394.1309, measured value: 395.1387 [M + H] ⁺

Example 40 4-{[5- (2,6-Diaminopyridin-4-yl) -2-methyl-3H-imidazo [4,5-b] pyridin-3-yl] methyl} benzonitrile According to general procedure II Starting from Preparation 2a, Example 40 was obtained using 4- (aminomethyl) benzonitrile as the appropriate amine. HRMS (IT-TOF, ESI) m / z: Calculated value of C ₂₀ H ₁₇ N ₇ 35.1545, measured value: 356.1612 [M + H] ⁺

Example 41 4- [2-Methyl-3- (tetrahydrofuran-3-ylmethyl) -3H-imidazo [4,5-b] pyridin-5-yl] pyridin-2,6-diamine Prepared according to general procedure II Starting from 2a, Example 41 was obtained using tetrahydrofuran-3-ylmethanamine as the appropriate amine. HRMS (IT-TOF, ESI) m / z: Calculated value of C ₁₇ H ₂₀ N ₆ O 324.1699, measured value: 325.1787 [M + H] ⁺

Example 42 4- [3- (Furan-3-ylmethyl) -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl] pyridin-2,6-diamine Prepared according to general procedure II Starting from 2a, Example 42 was obtained using 3-furylmethanamine as the appropriate amine. HRMS (IT-TOF, ESI) m / z: Calculated value of C ₁₇ H ₁₆ N ₆ O 320.1386, measured value: 321.1467 [M + H] ⁺

Example 43 4- {3- [4- (Difluoromethoxy) benzyl] -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl} pyridin-2,6-diamine According to general procedure II Example 43 was obtained starting from Preparation 2a using [4- (difluoromethoxy) phenyl] methanamine as the appropriate amine. HRMS (IT-TOF, ESI) m / z: Calculated value of C ₂₀ H ₁₈ N ₆ OF ₂ 396.1510, measured value: 397.11581 [M + H] ⁺

Example 44 4- {2-Methyl-3- [3- (methylsulfanyl) propyl] -3H-imidazo [4,5-b] pyridin-5-yl} pyridin-2,6-diamine According to general procedure II Starting from Preparation 2a, Example 44 was obtained using 3-methylsulfanylpropan-1-amine as the appropriate amine. HRMS (IT-TOF, ESI) m / z: Calculated value of C ₁₆ H ₂₀ N ₆ S 328.1470, measured value: 329.1551 [M + H] ⁺

Example 45 4- {2-Methyl-3-[(1,3,5-trimethyl-1H-pyrazol-4-yl) methyl] -3H-imidazo [4,5-b] pyridin-5-yl} pyridine -2,6-diamine Following general procedure II, starting from preparation 2a, using (1,3,5-trimethyl-1H-pyrazol-4-yl) methanamine as the appropriate amine, gives Example 45 . It was. HRMS (IT-TOF, ESI) m / z: Calculated value of C ₁₉ H ₂₂ N ₈ 362.1967, measured value: 363.2037 [M + H] ⁺

Example 46 4- [3- (2,5-Difluorobenzyl) -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl] pyridin-2,6-diamine Prepared according to general procedure II Example 46 was obtained starting from product 2a using (2,5-difluorophenyl) methanamine as the appropriate amine. HRMS (IT-TOF, ESI) m / z: Calculated value of C ₁₉ H ₁₆ N ₆ F ₂ 366.1405, measured value: 367.1484 [M + H] ⁺

Example 47 4- [3- (2-Chlorobenzyl) -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl] pyridin-2,6-diamine Preparation 2a according to general procedure II Starting from, Example 47 was obtained using (2-chlorophenyl) methanamine as the appropriate amine. HRMS (IT-TOF, ESI) m / z: Calculated value of C ₁₉ H ₁₇ N ₆ Cl 364.1203, measured value: 3655.1279 [M + H] ⁺

Example 48 4- [3- (3-Chlorobenzyl) -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl] pyridin-2,6-diamine Following general procedure II, preparation 2a Starting from, Example 48 was obtained using (3-chlorophenyl) methanamine as the appropriate amine. HRMS (IT-TOF, ESI) m / z: Calculated value of C ₁₉ H ₁₇ N ₆ Cl 364.1203, actual value: 3655.1277 [M + H] ⁺

Example 49 4- [2-Methyl-3- (tetrahydro-2H-pyran-4-yl) -3H-imidazo [4,5-b] pyridin-5-yl] pyridin-2,6-diamine General procedure II Example 49 was obtained starting from Preparation 2a using tetrahydro-2H-pyran-4-amine as the appropriate amine. HRMS (TOF, ESI) m / z: Calculated value of C ₁₇ H ₂₀ N ₆ O 324.1699, measured value: 325.1790 [M + H] ⁺

Example 50 4- {3- [2-Fluoro-5- (trifluoromethoxy) benzyl] -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl} pyridin-2,6-diamine Example 50 was obtained according to general procedure II starting from Preparation 2a using [2-fluoro-5- (trifluoromethoxy) phenyl] methanamine as the appropriate amine. HRMS (TOF, ESI) m / z: Calculated value of C ₂₀ H ₁₆ N ₆ OF ₄ 432.1322, measured value: 433.1416 [M + H] ⁺

Example 51 4- [2-Methyl-3- (prop-2-en-1-yl) -3H-imidazo [4,5-b] pyridin-5-yl] pyridin-2,6-diamine General procedure II Example 51 was obtained starting from Preparation 2a using prop-2-en-1-amine as the appropriate amine. HRMS (TOF, ESI) m / z: Calculated value of C ₁₅ H ₁₆ N ₆ 280.1436, measured value: 281.1524 [M + H] ⁺

Example 52 4- [3- (3,3-Dimethylbutyl) -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl] pyridin-2,6-diamine Prepared according to general procedure II Example 52 was obtained starting from product 2a using 3,3-dimethylbutan-1-amine as the appropriate amine. HRMS (TOF, ESI) m / z: Calculated value of C ₁₈ H ₂₄ N ₆ 324.2062, found value: 325.2153 [M + H] ⁺

Example 53 4- [2-Methyl-3- (propan-2-yl) -3H-imidazo [4,5-b] pyridin-5-yl] pyridin-2,6-diamine Prepared according to general procedure II Starting from 2a, Example 53 was obtained using propan-2-amine as the appropriate amine. HRMS (TOF, ESI) m / z: Calculated value of C ₁₅ H ₁₈ N ₆ 282.1593, measured value: 283.1675 [M + H] ⁺

Example 54 4- (3-cyclohexyl-2-methyl-3H-imidazo [4,5-b] pyridin-5-yl) pyridin-2,6-diamine According to general procedure II, starting from preparation 2a, Example 54 was obtained using cyclohexaneamine as the appropriate amine. HRMS (TOF, ESI) m / z: Calculated value of C ₁₈ H ₂₂ N ₆ 323.1921, measured value: 323.1994 [M + H] ⁺

Example 55 4- [3- (Cyclohexylmethyl) -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl] pyridin-2,6-diamine Starting from Preparation 2a according to general procedure II Example 55 was obtained using 1-cyclohexylmethanamine as the appropriate amine. HRMS (TOF, ESI) m / z: Calculated value of C ₁₉ H ₂₄ N ₆ 336.2062, found value: 337.2151 [M + H] ⁺

Example 56 4- {2-Methyl-3-tricyclo [3.3.1.1 ^3,7 ] dec-1-yl-3H-imidazo [4,5-b] pyridin-5-yl} pyridine-2 , 6-diamine Example 56 was obtained according to general procedure II starting from preparation 2a using 1-adamantylamine as the appropriate amine. _{HRMS (TOF, ESI) m /} z: C 22 H 26 N 6 [M + H] + Calculated 374.2219, Found: 375.2307.

Example 57 4- [3- (2,5-Dichlorobenzyl) -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl] pyridin-2,6-diamine Prepared according to general procedure II Example 57 was obtained starting from product 2a using (2,5-dichlorophenyl) methanamine as the appropriate amine. HRMS (TOF, ESI) m / z: Calculated value of C ₁₉ H ₁₆ N ₆ Cl ₂ 398.814, found value: 399.0896 [M + H] ⁺

Example 58 4- {3- [2- (3,4-Dichlorophenyl) ethyl] -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl} pyridin-2,6-diamine General procedure Example 58 was obtained according to II starting from Preparation 2a using 2- (3,4-dichlorophenyl) ethanamine as the appropriate amine. HRMS (TOF, ESI) m / z: Calculated value of C ₂₀ H ₁₈ N ₆ Cl ₂ 412.0970, measured value: 413.1105 [M + H] ⁺

Example 59 4- {3- [2- (2,4-Dichlorophenyl) ethyl] -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl} pyridin-2,6-diamine General procedure Example 59 was obtained according to II, starting from Preparation 2a, using 2- (2,4-dichlorophenyl) ethanamine as the appropriate amine. HRMS (TOF, ESI) m / z: Calculated value of C ₂₀ H ₁₈ N ₆ Cl ₂ 412.097, measured value: 413.1068 [M + H] ⁺

Example 60 4- [2-Methyl-3- (2-phenylpropan-2-yl) -3H-imidazo [4,5-b] pyridin-5-yl] pyridin-2,6-diamine and
Example 61 4- (2-Methyl-3H-imidazo [4,5-b] pyridin-5-yl) pyridin-2,6-diamine Following general procedure II, starting from preparation 2a as the appropriate amine Example 60 was obtained using 2-phenylpropan-2-amine. HRMS (TOF, ESI) m / z: Calculated for C ₂₁ H ₂₂ N ₆ 358.1906, found: 359.1988 [M + H] ⁺ Example 61 was also isolated from the same reaction. _{HRMS (TOF, ESI) m /} z: Calculated for _{C 12 H 12 N 6} 240.1123, Found: 241.1206. [M + H] ⁺

Example 62 4- [2-Methyl-3- (1,2,3,4-tetrahydronaphthalen-1-yl) -3H-imidazo [4,5-b] pyridin-5-yl] pyridin-2,6 -Diamine Example 62 was obtained according to General Procedure II, starting from Preparation 2a, using 1,2,3,4-tetrahydronaphthalen-1-amine as the appropriate amine. HRMS (TOF, ESI) m / z: Calculated value of C ₂₂ H ₂₂ N ₆ 370.1906, measured value: 371.1989 [M + H] ⁺

Example 63 4- {2-Methyl-3- [2- (2-methylphenyl) ethyl] -3H-imidazo [4,5-b] pyridin-5-yl} pyridin-2,6-diamine General procedure II Example 63 was obtained starting from Preparation 2a using 2- (o-tolyl) ethanamine as the appropriate amine. HRMS (TOF, ESI) m / z: Calculated value of C ₂₁ H ₂₂ N ₆ 358.1906, measured value: 359.1985 [M + H] ⁺

Example 64 4- [2-Methyl-3- (pentan-2-yl) -3H-imidazo [4,5-b] pyridin-5-yl] pyridin-2,6-diamine Prepared according to general procedure II Example 64 was obtained starting from 2a using pentan-2-amine as the appropriate amine. HRMS (TOF, ESI) m / z: Calculated value of C ₁₇ H ₂₂ N ₆ 310.1906, measured value: 311.1980 [M + H] ⁺

Example 65 4- (2-Methyl-3-pentyl-3H-imidazo [4,5-b] pyridin-5-yl) pyridin-2,6-diamine According to general procedure II, starting from preparation 2a, Example 65 was obtained using pentan-1-amine as the appropriate amine. HRMS (TOF, ESI) m / z: Calculated value of C ₁₇ H ₂₂ N ₆ 310.1906, measured value: 311.1983 [M + H] ⁺

Example 66 4- [2-Methyl-3- (tetrahydro-2H-thiopyran-4-yl) -3H-imidazo [4,5-b] pyridin-5-yl] pyridin-2,6-diamine General procedure II Example 66 was obtained starting from Preparation 2a using tetrahydro-2H-thiopyran-4-amine as the appropriate amine. HRMS (TOF, ESI) m / z: Calculated value of C ₁₇ H ₂₀ N ₆ S 340.147, measured value: 341.1545 [M + H] ⁺

Example 67 4- [2-Methyl-3- (1-phenylpropyl) -3H-imidazo [4,5-b] pyridin-5-yl] pyridin-2,6-diamine Following general procedure II, preparation 2a Example 67 was obtained starting from and using 1-phenylpropan-1-amine as the appropriate amine. HRMS (TOF, ESI) m / z: Calculated value of C ₂₁ H ₂₂ N ₆ 358.1906, measured value: 359.1979 [M + H] ⁺

Example 68 4- [2-Methyl-3- (pentan-3-yl) -3H-imidazo [4,5-b] pyridin-5-yl] pyridin-2,6-diamine Prepared according to general procedure II Example 68 was obtained starting from 2a using pentane-3-amine as the appropriate amine. HRMS (TOF, ESI) m / z: Calculated value of C ₁₇ H ₂₂ N ₆ 310.1906, measured value: 311.1985 [M + H] ⁺

Example 69 4- {3- [3- (2-methoxyphenyl) propyl] -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl} pyridin-2,6-diamine General procedure II Example 69 was obtained starting from preparation 2a using 3- (2-methoxyphenyl) propan-1-amine as the appropriate amine. HRMS (TOF, ESI) m / z: Calculated value of C ₂₂ H ₂₄ N ₆ O 388.2012, measured value: 389.2095 [M + H] ⁺

Example 70 4- [5- (2,6-Diaminopyridin-4-yl) -2-methyl-3H-imidazo [4,5-b] pyridin-3-yl] butan-1-ol According to general procedure II Starting from Preparation 2a, Example 70 was obtained using 4-aminobutan-1-ol as the appropriate amine. HRMS (TOF, ESI) m / z: Calculated value of C ₁₆ H ₂₀ N ₆ O 312.1699, measured value: 313.1767 [M + H] ⁺

Example 71 4- [2-Methyl-3- (4,4,4-trifluorobutyl) -3H-imidazo [4,5-b] pyridin-5-yl] pyridin-2,6-diamine General procedure II Example 71 was obtained starting from Preparation 2a using 4,4,4-trifluorobutan-1-amine as the appropriate amine. HRMS (TOF, ESI) m / z: Calculated value of C ₁₆ H ₁₇ N ₆ F ₃ 350.1467, measured value: 351.1533 [M + H] ⁺

Example 72 4- {3-[(2-methoxypyridin-4-yl) methyl] -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl} pyridin-2,6-diamine General Example 72 was obtained according to Procedure II, starting from Preparation 2a, using (2-methoxy-4-pyridyl) methanamine as the appropriate amine. HRMS (TOF, ESI) m / z: Calculated value of C ₁₉ H ₁₉ N ₇ O 361.1651, measured value: 362.1726 [M + H] ⁺

Example 73 4- {3- [2- (1,3-benzodioxol-5-yl) ethyl] -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl} pyridine- 2,6-diamine Example 73 was obtained according to General Procedure II, starting from Preparation 2a, using 2- (1,3-benzodioxol-5-yl) ethanamine as the appropriate amine. HRMS (TOF, ESI) m / z: Calculated value of C ₂₁ H ₂₀ N ₆ O ₂ 388.1648, measured value: 389.1728 [M + H] ⁺

Example 74 4- {3-[(2,2-dichlorocyclopropyl) methyl] -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl} pyridin-2,6-diamine General procedure Example 74 was obtained according to II starting from Preparation 2a using (2,2-dichlorocyclopropyl) methanamine as the appropriate amine. HRMS (TOF, ESI) m / z: Calculated value of C ₁₆ H ₁₆ N ₆ Cl ₂ 362.0814, measured value: 363.0883 [M + H] ⁺

Example 75 4- [2-Methyl-3- (3-methylbutyl) -3H-imidazo [4,5-b] pyridin-5-yl] pyridin-2,6-diamine Following general procedure II, from Preparation 2a Starting, Example 75 was obtained using 3-methylbutan-1-amine as the appropriate amine. HRMS (TOF, ESI) m / z: Calculated value of C ₁₇ H ₂₂ N ₆ 310.1906, measured value: 311.1990 [M + H] ⁺

Example 76 4- [2-Methyl-3- (tetrahydro-2H-pyran-3-ylmethyl) -3H-imidazo [4,5-b] pyridin-5-yl] pyridin-2,6-diamine General procedure II The Example 76 was obtained starting from Preparation 2a using tetrahydro-2H-pyran-3-ylmethanamine as the appropriate amine. HRMS (TOF, ESI) m / z: Calculated value of C ₁₈ H ₂₂ N ₆ O 338.1855, actual value: 339.1944 [M + H] ⁺

Example 77 4- {3- [2- (2,3-dihydro-1,4-benzodioxin-6-yl) ethyl] -2-methyl-3H-imidazo [4,5-b] pyridine-5 Yl} pyridin-2,6-diamine Following general procedure II, starting from preparation 2a, using 2- (2,3-dihydro-1,4-benzodioxin-6-yl) ethanamine as the appropriate amine Example 77 was obtained. HRMS (TOF, ESI) m / z: Calculated value of C ₂₂ H ₂₂ N ₆ O ₂ 402.804, measured value: 403.1888 [M + H] ⁺

Example 78 4- {2-Methyl-3- [2- (tetrahydro-2H-pyran-4-yl) ethyl] -3H-imidazo [4,5-b] pyridin-5-yl} pyridine-2,6 -Diamine Example 78 was obtained according to general procedure II starting from Preparation 2a with 2-tetrahydro-2H-pyran-4-ylethanamine as the appropriate amine. HRMS (TOF, ESI) m / z: Calculated value of C ₁₉ H ₂₄ N ₆ O 352.2012, measured value: 353.2080 [M + H] ⁺

Example 79 4- (2-methyl-3- {2- [2- (trifluoromethyl) phenyl] ethyl} -3H-imidazo [4,5-b] pyridin-5-yl) pyridin-2,6- Diamine Example 79 was obtained according to General Procedure II, starting from Preparation 2a, using 2- [2- (trifluoromethyl) phenyl] ethanamine as the appropriate amine. HRMS (TOF, ESI) m / z: Calculated value of C ₂₁ H ₁₉ N ₆ F ₃ 412.1623, measured value: 413.1708 [M + H] ⁺

Example 80 4- [2-Methyl-3- (tetrahydro-2H-pyran-4-ylmethyl) -3H-imidazo [4,5-b] pyridin-5-yl] pyridin-2,6-diamine General procedure II Example 80 was obtained starting from Preparation 2a using tetrahydro-2H-pyran-4-ylmethanamine as the appropriate amine. HRMS (TOF, ESI) m / z: Calculated value of C ₁₈ H ₂₂ N ₆ O 338.1855, actual value: 339.1929 [M + H] ⁺

Example 81 4- {3- [2- (2-methoxyphenyl) ethyl] -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl} pyridin-2,6-diamine General procedure II Example 81 was obtained starting from Preparation 2a, using 2- (2-methoxyphenyl) ethanamine as the appropriate amine. HRMS (TOF, ESI) m / z: Calculated value of C ₂₁ H ₂₂ N ₆ O 3744.1855, measured value: 375.1924 [M + H] ⁺

Example 82 4- {3- [1- (furan-2-yl) propan-2-yl] -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl} pyridin-2,6 -Diamine Example 82 was obtained according to general procedure II, starting from preparation 2a, using 1- (2-furyl) propan-2-amine as the appropriate amine. HRMS (TOF, ESI) m / z: Calculated value of C ₁₉ H ₂₀ N ₆ O 348.1699, measured value: 349.1772 [M + H] ⁺

Example 83 4- [2-Methyl-3- (2-phenylethyl) -3H-imidazo [4,5-b] pyridin-5-yl] pyridin-2,6-diamine Following general procedure II, preparation 2a Starting from, Example 83 was obtained using 2-phenyl-ethylamine as the appropriate amine. HRMS (TOF, ESI) m / z: Calculated value of C ₂₀ H ₂₀ N ₆ 344.1749, measured value: 345.1829 [M + H] ⁺

Example 84 4- {3-[(2-Fluoropyridin-4-yl) methyl] -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl} pyridin-2,6-diamine General Example 84 was obtained according to Procedure II, starting from Preparation 2a, using (2-fluoro-4-pyridyl) methanamine as the appropriate amine. HRMS (TOF, ESI) m / z: Calculated value of C ₁₈ H ₁₆ N ₇ F 349.1451, measured value: 350.1531 [M + H] ⁺

Example 85 4- {2-Methyl-3- [2- (tetrahydrofuran-2-yl) ethyl] -3H-imidazo [4,5-b] pyridin-5-yl} pyridin-2,6-diamine General procedure Example 85 was obtained according to II, starting from Preparation 2a, using 2-tetrahydrofuran-2-ylethanamine as the appropriate amine. HRMS (TOF, ESI) m / z: Calculated value of C ₁₈ H ₂₂ N ₆ O 338.1855, measured value: 399.1930 [M + H] ⁺

Example 86 4- {2-Methyl-3-[(2-methylcyclopropyl) methyl] -3H-imidazo [4,5-b] pyridin-5-yl} pyridin-2,6-diamine According to general procedure II Starting from Preparation 2a, Example 86 was obtained using 1- (2-methylcyclopropyl) methanamine as the appropriate amine. HRMS (TOF, ESI) m / z: Calculated value of C ₁₇ H ₂₀ N ₆ 308.149, actual value: 309.1822 [M + H] ⁺

Example 87 4- (2-methyl-3- {2- [3- (propan-2-yloxy) phenyl] ethyl} -3H-imidazo [4,5-b] pyridin-5-yl) pyridine-2, 6-diamine Example 87 was obtained according to General Procedure II, starting from Preparation 2a, using 2- (3-isopropoxyphenyl) ethanamine as the appropriate amine. HRMS (TOF, ESI) m / z: Calculated value of C ₂₃ H ₂₆ N ₆ O 402.2168, measured value: 403.2153 [M + H] ⁺

Example 88 4- {3-[(1-ethylcyclopropyl) methyl] -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl} pyridin-2,6-diamine According to general procedure II Starting from Preparation 2a, Example 88 was obtained using 1- (1-ethylcyclopropyl) methanamine as the appropriate amine. HRMS (TOF, ESI) m / z: Calculated value of C ₁₈ H ₂₂ N ₆ 322.1906, measured value: 323.1988 [M + H] ⁺

Example 89 4- [3- (Cyclopentylmethyl) -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl] pyridin-2,6-diamine Starting from Preparation 2a according to general procedure II Example 89 was obtained using cyclopentylmethanamine as the appropriate amine. HRMS (TOF, ESI) m / z: Calculated value of C ₁₈ H ₂₂ N ₆ 322.1906, measured value: 323.1987 [M + H] ⁺

Example 90 4- {3- [2- (3-Ethoxyphenyl) ethyl] -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl} pyridin-2,6-diamine General procedure II Example 90 was obtained starting from Preparation 2a using 2- (3-ethoxyphenyl) ethanamine as the appropriate amine. HRMS (TOF, ESI) m / z: Calculated value of C ₂₂ H ₂₄ N ₆ O 388.2012, measured value: 389.1953 [M + H] ⁺

Example 91 4- (2-Methyl-3- {2- [3- (trifluoromethyl) phenyl] ethyl} -3H-imidazo [4,5-b] pyridin-5-yl) pyridin-2,6- Diamine Example 91 was obtained according to General Procedure II, starting from Preparation 2a, using 2- [3- (trifluoromethyl) phenyl] ethanamine as the appropriate amine. HRMS (TOF, ESI) m / z: Calculated value of C ₂₁ H ₁₉ N ₆ F ₃ 412.1623, measured value: 413.1683 [M + H] ⁺

Example 92 4- [3- (2-Cyclopentylethyl) -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl] pyridin-2,6-diamine Following general procedure II, preparation 2a Example 92 was obtained starting from and using 2-cyclopentylethanamine as the appropriate amine. HRMS (TOF, ESI) m / z: Calculated value of C ₁₉ H ₂₄ N ₆ 336.2062, found value: 337.2012 [M + H] ⁺

Example 93 4- [3- (5-Methoxy-1,2,3,4-tetrahydronaphthalen-2-yl) -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl] pyridine -2,6-diamine Example 93 was obtained according to general procedure II starting from Preparation 2a using 5-methoxytetralin-2-amine as the appropriate amine. HRMS (TOF, ESI) m / z: Calculated value of C ₂₃ H ₂₄ N ₆ O 400.0212, measured value: 401.1963 [M + H] ⁺

Example 94 4- (3-Hexyl-2-methyl-3H-imidazo [4,5-b] pyridin-5-yl) pyridin-2,6-diamine According to general procedure II, starting from preparation 2a, Example 94 was obtained using hexane-1-amine as the appropriate amine. HRMS (TOF, ESI) m / z: Calculated value of C ₁₈ H ₂₄ N ₆ 324.2062, found value: 325.2014 [M + H] ⁺

Example 95 4- {3- [2- (2-methoxycyclohexyl) ethyl] -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl} pyridin-2,6-diamine General procedure II Example 95 was obtained starting from Preparation 2a using 2- (2-methoxycyclohexyl) ethanamine as the appropriate amine. HRMS (TOF, ESI) m / z: Calculated value of C ₂₁ H ₂₈ N ₆ O 380.2325, measured value: 381.2378 [M + H] ⁺

Example 96 4- {3- [2- (4-Fluorophenyl) ethyl] -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl} pyridin-2,6-diamine General procedure II Example 96 was obtained starting from Preparation 2a, using 2- (4-fluorophenyl) ethanamine as the appropriate amine. HRMS (TOF, ESI) m / z: Calculated value of C ₂₀ H ₁₉ N ₆ F 362.1655, measured value: 363.1726 [M + H] ⁺

Example 97 4- {2-Methyl-3-[(2-phenylcyclopropyl) methyl] -3H-imidazo [4,5-b] pyridin-5-yl} pyridin-2,6-diamine According to general procedure II Starting from Preparation 2a, Example 97 was obtained using 1- (2-phenylcyclopropyl) methanamine as the appropriate amine. HRMS (TOF, ESI) m / z: Calculated value of C ₂₂ H ₂₂ N ₆ 370.1906, measured value: 371.1976 [M + H] ⁺

Example 98 4- [3- (5-Methoxy-2,3-dihydro-1H-inden-2-yl) -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl] pyridine- 2,6-diamine Example 98 was obtained according to General Procedure II, starting from Preparation 2a, using 5-methoxyindan-2-amine as the appropriate amine. HRMS (TOF, ESI) m / z: Calculated value of C ₂₂ H ₂₂ N ₆ O 3866.1855, measured value: 387.1818 [M + H] ⁺

Example 99 4- {3-[(2,2-dimethylcyclopropyl) methyl] -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl} pyridin-2,6-diamine General procedure Example 99 was obtained according to II starting from Preparation 2a using 1- (2,2-dimethylcyclopropyl) methanamine as the appropriate amine. HRMS (TOF, ESI) m / z: Calculated value of C ₁₈ H ₂₂ N ₆ 322.1906, measured value: 323.1978 [M + H] ⁺

Example 100 4- [2-Methyl-3- (3-phenylcyclobutyl) -3H-imidazo [4,5-b] pyridin-5-yl] pyridin-2,6-diamine Prepared according to general procedure II Starting from 2a, Example 100 was obtained using 3-phenylcyclobutanamine as the appropriate amine. HRMS (TOF, ESI) m / z: Calculated value of C ₂₂ H ₂₂ N ₆ 370.1906, measured value: 371.1978 [M + H] ⁺

Example 101 4- [3- (3,3-Difluorocyclobutyl) -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl] pyridin-2,6-diamine According to general procedure II Starting from Preparation 2a, Example 101 was obtained using 3,3-difluorocyclobutaneamine as the appropriate amine. HRMS (TOF, ESI) m / z: Calculated value of C ₁₆ H ₁₆ N ₆ F ₂ 330.1405, measured value: 331.1463 [M + H] ⁺

Example 102 4- {2-Methyl-3- [2- (2-methylcyclohexyl) ethyl] -3H-imidazo [4,5-b] pyridin-5-yl} pyridin-2,6-diamine General procedure II Example 102 was obtained starting from Preparation 2a using 2- (2-methylcyclohexyl) ethanamine as the appropriate amine. _{HRMS (TOF, ESI) m /} z: Calculated for _{C 21 H} 28 _{N 6} 364.2375, Found: about two diastereoisomers, 365.2447 and 365.2436 [M + ^H] +.

Example 103 4- [3- (3-Fluorocyclobutyl) -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl] pyridine-2,6-diamine Prepared according to general procedure II Starting from 2a, Example 103 was obtained using 3-fluorocyclobutaneamine as the appropriate amine. HRMS (TOF, ESI) m / z: Calculated value of C ₁₆ H ₁₇ N ₆ F 312.1499, measured value: 313.1566 [M + H] ⁺

Example 104 4- {2-Methyl-3-[(2R) -1-phenoxypropan-2-yl] -3H-imidazo [4,5-b] pyridin-5-yl} pyridin-2,6-diamine as well as
Example 105 4- {2-Methyl-3-[(2S) -1-phenoxypropan-2-yl] -3H-imidazo [4,5-b] pyridin-5-yl} pyridin-2,6-diamine Following the general procedure II, starting from Preparation 2a, using 1-phenoxypropan-2-amine as the appropriate amine, a mixture of Example 104 and Example 105 was obtained. The enantiomers were separated on a CHIRALCEL OK column using MeOH + 0.1% DEA as the eluent to give Example 104 as the first eluting enantiomer. HRMS (TOF, ESI) m / z: Calculated value of C ₂₁ H ₂₂ N ₆ O 3744.1855, found value: 375.1913 [M + H] ⁺ ee> 99.8% (E1). Example 105 was obtained as the second eluting enantiomer. HRMS (TOF, ESI) m / z: Calculated value of C ₂₁ H ₂₂ N ₆ O 374.1844, measured value: 375.1919 [M + H] ⁺ ee = 98.4% (E2)

Example 106 4- {2-methyl-3-[(2R) -2-phenoxypropyl] -3H-imidazo [4,5-b] pyridin-5-yl} pyridin-2,6-diamine and
Example 107 4- {2-Methyl-3-[(2S) -2-phenoxypropyl] -3H-imidazo [4,5-b] pyridin-5-yl} pyridin-2,6-diamine According to general procedure II Starting from Preparation 2a, a mixture of Example 106 and Example 107 was obtained using 2-phenoxypropan-1-amine as the appropriate amine. The enantiomers were separated on a CHIRALCEL OK column using MeOH + 0.1% DEA as the eluent to give Example 106 as the first eluting enantiomer. _{HRMS (TOF, ESI) m /} z: C 21 H 22 N 6 O Calculated 374.1855, Found: 375.1924. [M + H] ⁺ ee> 99.8% (E1). Example 107 was obtained as the second eluting enantiomer. HRMS (TOF, ESI) m / z: Calculated value of C ₂₁ H ₂₂ N ₆ O 3744.1855, measured value: 375.1922 [M + H] ⁺ ee> 99.8% (E2)

Example 108 4- [2-Methyl-3- (3,3,3-trifluoropropyl) -3H-imidazo [4,5-b] pyridin-5-yl] pyridin-2,6-diamine General procedure II Example 108 was obtained starting from Preparation 2a using 3,3,3-trifluoropropan-1-amine as the appropriate amine. HRMS (IT-TOF, ESI) m / z: Calculated value of C ₁₅ H ₁₅ N ₆ F ₃ 336.131, measured value: 337.1138 [M + H] ⁺

Example 109 4- (2-methyl-3-{[(1S, 2S) -2-phenylcyclopropyl] methyl} -3H-imidazo [4,5-b] pyridin-5-yl) pyridin-2,6 -Diamines and
Example 110 4- (2-Methyl-3-{[(1R, 2R) -2-phenylcyclopropyl] methyl} -3H-imidazo [4,5-b] pyridin-5-yl) pyridin-2,6 -Diamine Following the general procedure II, starting from Preparation 2a, using [1,2-trans-2-phenylcyclopropyl] methanamine as the appropriate amine, a mixture of Example 109 and Example 110 was obtained. The enantiomers were separated on a CHIRALCEL OD-H column using 40:60 1-PrOH / heptane + 0.1% DEA as the eluent to give Example 109 as the first eluting enantiomer. HRMS (IT-TOF, ESI) m / z: Calculated value for C ₂₂ H ₂₂ N ₆ 370.1906, found value: 371.1981 [M + H] ⁺ ee> 99.8% (E1). Example 110 was obtained as the second eluting enantiomer. HRMS (IT-TOF, ESI) m / z: Calculated value for C ₂₂ H ₂₂ N ₆ 370.1906, found value: 371.1984 [M + H] ⁺ ee> 99.8% (E2).

Example 111 4- {2-Methyl-3-[(2E) -3-phenylprop-2-en-1-yl] -3H-imidazo [4,5-b] pyridin-5-yl} pyridine-2 , 6-diamine Example 111 was obtained according to general procedure II starting from preparation 2a using (E) -3-phenylprop-2-en-1-amine as the appropriate amine. HRMS (IT-TOF, ESI) m / z: Calculated value of C ₂₁ H ₂₀ N ₆ 356.1749, measured value: 357.1828 [M + H] ⁺

Example 112 4- [3- (bicyclo [4.2.0] octa-1,3,5-trien-7-ylmethyl) -2-methyl-3H-imidazo [4,5-b] pyridine-5 Yl] pyridine-2,6-diamine and
Example 113 4- [3- (bicyclo [4.2.0] octa-1,3,5-trien-7-ylmethyl) -2-methyl-3H-imidazo [4,5-b] pyridine-5 Yl] pyridine-2,6-diamine Starting from Preparation 2a according to general procedure II, 1- (bicyclo [4.2.0] octa-1,3,5-trien-7-yl as the appropriate amine with methanamine, the. enantiomer to obtain a mixture of example 112 to example 113, and separated by CHIRALPAK aS-H column with 50:50 EtOH / heptane + 0.1% DEA as eluent example 112 was obtained as the first eluting enantiomer 112. HRMS (IT-TOF, ESI) m / z: Calculated for C ₂₁ H ₂₀ N ₆ 356.1749, found: 357.818 [M + H] ⁺ ee> 99.8% (E1) Example 113 was obtained as the second eluting enantiomer, HRMS (IT-TOF, ESI) m / z: Calculated for C ₂₁ H ₂₀ N ₆ 356 .1749, found: 357.1810 [M + H] ⁺ ee = 99.6% (E2).

Example 114 4- [3- (2,3-dihydro-1H-inden-2-ylmethyl) -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl] pyridin-2,6- Diamine Example 114 was obtained according to General Procedure II, starting from Preparation 2a, using indan-2-ylmethanamine as the appropriate amine. HRMS (IT-TOF, ESI) m / z: Calculated value of C ₂₂ H ₂₂ N ₆ 370.1906, measured value: 371.1962 [M + H] ⁺

Example 115 4- [3- (2,2-Difluoroethyl) -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl] pyridin-2,6-diamine Prepared according to general procedure II Example 115 was obtained starting from product 2a using 2,2-difluoroethanamine as the appropriate amine. HRMS (TOF, ESI) m / z: Calculated value of C ₁₄ H ₁₄ N ₆ F ₂ 304.1248, measured value: 305.1318 [M + H] ⁺

Example 116 4- [2-Methyl-3- (2-methyl-2-phenoxypropyl) -3H-imidazo [4,5-b] pyridin-5-yl] pyridin-2,6-diamine According to general procedure II Starting from Preparation 2a, Example 116 was obtained using 2-methyl-2-phenoxy-propan-1-amine as the appropriate amine. HRMS (IT-TOF, ESI) m / z: Calculated value of C ₂₂ H ₂₄ N ₆ O 388.2012, measured value: 389.2069 [M + H] ⁺

Example 117 4- {3-[(2S) -2- (2-chlorophenoxy) propyl] -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl} pyridine-2,6- Diamines and
Example 118 4- {3-[(2R) -2- (2-chlorophenoxy) propyl] -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl} pyridin-2,6- Diamine Following the general procedure II, starting from Preparation 2a, using 2- (2-chlorophenoxy) propan-1-amine as the appropriate amine, a mixture of Example 117 and Example 118 was obtained. The enantiomers were separated on a CHIRALPAK AS-H column using 50:50 EtOH / heptane + 0.1% DEA as the eluent to give Example 117 as the first eluting enantiomer. HRMS (IT-TOF, ESI) m / z: Calculated value of C ₂₁ H ₂₁ N ₆ OCl 408.1465, found value: 409.1558 [M + H] ⁺ ee> 99.8% (E1). Example 118 was obtained as the second eluting enantiomer. HRMS (IT-TOF, ESI) m / z: Calculated value of C ₂₁ H ₂₁ N ₆ OCl 408.1465, found value: 409.1538 [M + H] ⁺ ee = 99.8% (E2).

Example 119 4- {2-methyl-3-[(2S) -2-phenoxybutyl] -3H-imidazo [4,5-b] pyridin-5-yl} pyridin-2,6-diamine and
Example 120 4- {2-Methyl-3-[(2R) -2-phenoxybutyl] -3H-imidazo [4,5-b] pyridin-5-yl} pyridin-2,6-diamine According to general procedure II Starting from Preparation 2a, a mixture of Example 119 and Example 120 was obtained using 2-phenoxybutan-1-amine as the appropriate amine. The enantiomers were separated on a CHIRALPAK AS-V column using 40:60 EtOH / heptane + 0.05% DEA as the eluent to give Example 119 as the first eluting enantiomer. HRMS (TOF, ESI) m / z: Calculated value for C ₂₂ H ₂₄ N ₆ O 388.2012, found value: 389.2084 [M + H] ⁺ ee> 99.8% (E1). Example 120 was obtained as the second eluting enantiomer. HRMS (TOF, ESI) m / z: Calculated value for C ₂₂ H ₂₄ N ₆ O 388.2012, found value: 389.2093 [M + H] ⁺ ee = 99.2% (E2).

Example 121 4- (2-Methyl-3-{(2R) -2- [methyl (phenyl) amino] propyl} -3H-imidazo [4,5-b] pyridin-5-yl) pyridin-2,6 -Diamines and
Example 122 4- (2-methyl-3-{(2S) -2- [methyl (phenyl) amino] propyl} -3H-imidazo [4,5-b] pyridin-5-yl) pyridin-2,6 - according diamine general procedure II, the starting from the preparation 2a, as appropriate amine ^{N 2} - methyl -N ² - phenyl - using propane-1,2-diamine a mixture of example 121 example 122 Obtained. The enantiomers were separated on a CHIRALPAK IA column using 20:80 EtOH / heptane + 0.1% DEA as the eluent to give Example 122 as the first eluting enantiomer. HRMS (IT-TOF, ESI) m / z: Calculated value for C ₂₂ H ₂₅ N ₇ 3877.271, found value: 388.2253 [M + H] ⁺ ee> 99.8% (E1). Example 121 was obtained as the second eluting enantiomer. HRMS (IT-TOF, ESI) m / z: Calculated value of C ₂₂ H ₂₅ N ₇ 387.2171, measured value: 388.2232 [M + H] ⁺ ee> 99.8% (E2)

Example 123 4- {3-[(2S) -2- (3-fluorophenoxy) propyl] -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl} pyridin-2,6- Diamines and
Example 124 4- {3-[(2R) -2- (3-fluorophenoxy) propyl] -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl} pyridin-2,6- Diamine Following the general procedure II, starting from Preparation 2a, using 2- (3-fluorophenoxy) propan-1-amine as the appropriate amine, a mixture of Example 123 and Example 124 was obtained. The enantiomers were separated on a CHIRALCEL OJ-H column using EtOH + 0.1% DEA as the eluent to give Example 123 as the first eluting enantiomer. HRMS (IT-TOF, ESI) m / z: Calculated value of C ₂₁ H ₂₁ N ₆ OF 392.1761, found value: 393.1850 [M + H] ⁺ ee> 99.8% (E1). Example 124 was obtained as the second eluting enantiomer. HRMS (IT-TOF, ESI) m / z: Calculated value of C ₂₁ H ₂₁ N ₆ OF 392.1761, found value: 393.1828 [M + H] ⁺ ee = 99.8% (E2).

Example 125 4- {3-[(2S) -2- (3-methoxyphenoxy) propyl] -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl} pyridin-2,6- Diamines and
Example 126 4- {3-[(2R) -2- (3-methoxyphenoxy) propyl] -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl} pyridin-2,6- Diamine Following the general procedure II, starting from Preparation 2a, using 2- (3-methoxyphenoxy) propan-1-amine as the appropriate amine, a mixture of Example 125 and Example 126 was obtained. The enantiomers were separated on a CHIRALPAK AS-H column to give Example 125 as the first enantiomer to elute. HRMS (IT-TOF, ESI) m / z: Calculated value for C ₂₂ H ₂₄ N ₆ O ₂ 404.1961, found value: 405.2040 [M + H] ⁺ ee> 99.8% (E1). Example 126 was obtained as the second eluting enantiomer. _{HRMS (IT-TOF, ESI)} m / z: C 22 H 24 N 6 O 2 Calculated 404.1961, ^{Found: 405.2048 [M + H] +} ee = 99.6% (E2).

Example 127 4- {2-methyl-3-[(2S) -2- (3-methylphenoxy) propyl] -3H-imidazo [4,5-b] pyridin-5-yl} pyridin-2,6- Diamines and
Example 128 4- {2-methyl-3-[(2R) -2- (3-methylphenoxy) propyl] -3H-imidazo [4,5-b] pyridin-5-yl} pyridine-2,6- Diamine Following the general procedure II, starting from Preparation 2a, using 2- (3-methylphenoxy) propan-1-amine as the appropriate amine, a mixture of Example 127 and Example 128 was obtained. The enantiomers were separated on a CHIRALPAK AS-V column using 50:50 EtOH / heptane + 0.05% DEA as the eluent to give Example 127 as the first eluting enantiomer. HRMS (IT-TOF, ESI) m / z: Calculated value of C ₂₂ H ₂₄ N ₆ O 388.2012, measured value: 389.2088. [M + H] ⁺ ee> 99.8% (E1). Example 128 was obtained as the second eluting enantiomer. HRMS (IT-TOF, ESI) m / z: Calculated value for C ₂₂ H ₂₄ N ₆ O 388.2012, found value: 389.2079. [M + H] ⁺ ee = 99.2% (E2).

Example 129 4- {3-[(2S) -2- (4-fluorophenoxy) propyl] -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl} pyridine-2,6- Diamines and
Example 130 4- {3-[(2R) -2- (4-fluorophenoxy) propyl] -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl} pyridin-2,6- Diamine Following the general procedure II, starting from Preparation 2a, using 2- (4-fluorophenoxy) propan-1-amine as the appropriate amine, a mixture of Example 129 and Example 130 was obtained. The enantiomers were separated on a CHIRALPAK AS-V column using 50:50 EtOH / heptane + 0.05% DEA as the eluent to give Example 129 as the first eluting enantiomer. HRMS (IT-TOF, ESI) m / z: Calculated value for C ₂₁ H ₂₁ N ₆ OF 392.1761, found value: 393.1832. [M + H] ⁺ ee> 99.8% (E1). Example 130 was obtained as the second eluting enantiomer. HRMS (IT-TOF, ESI) m / z: Calculated value of C ₂₁ H ₂₁ N ₆ OF 392.1761, found value: 393.1834. [M + H] ⁺ ee = 99.8% (E2).

Example 131 4- {2-methyl-3-[(2S) -2- (2-methylphenoxy) propyl] -3H-imidazo [4,5-b] pyridin-5-yl} pyridine-2,6- Diamines and
Example 132 4- {2-methyl-3-[(2R) -2- (2-methylphenoxy) propyl] -3H-imidazo [4,5-b] pyridin-5-yl} pyridin-2,6- Diamine According to General Procedure II, starting from Preparation 2a, using 2- (2-methylphenoxy) propan-1-amine as the appropriate amine, a mixture of Example 131 and Example 132 was obtained. The enantiomer was separated on an OJ column using EtOH + 0.05% DEA as the eluent to give Example 131 as the first eluting enantiomer. HRMS (IT-TOF, ESI) m / z: Calculated value for C ₂₂ H ₂₄ N ₆ O 388.2012, found value: 389.2103 [M + H] ⁺ ee> 99.8% (E1). Example 132 was obtained as the second eluting enantiomer. _{HRMS (IT-TOF, ESI)} m / z: C 22 H 24 N 6 O Calculated 388.2012, ^{Found: 389.2081 [M + H] +} ee = 99.0% (E2).

Example 133 4- {3-[(2S) -2- (2-fluorophenoxy) propyl] -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl} pyridine-2,6- Diamines and
Example 134 4- {3-[(2R) -2- (2-fluorophenoxy) propyl] -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl} pyridin-2,6- Diamine According to General Procedure II, starting from Preparation 2a, using 2- (2-fluorophenoxy) propan-1-amine as the appropriate amine, a mixture of Example 133 and Example 134 was obtained. The enantiomers were separated on a CHIRALPAK AS-V column using 70:30 EtOH / heptane + 0.05% DEA as the eluent to give Example 133 as the first eluting enantiomer. HRMS (IT-TOF, ESI) m / z: Calculated value of C ₂₁ H ₂₁ N ₆ OF 392.1761, found value: 393.1836 [M + H] ⁺ ee> 99.8% (E1). Example 134 was obtained as the second eluting enantiomer. HRMS (IT-TOF, ESI) m / z: Calculated value of C ₂₁ H ₂₁ N ₆ OF 392.1761, measured value: 393.1852. [M + H] ⁺ ee = 99.6% (E2).

Example 135 4- {2-methyl-3-[(2S) -2- (phenylsulfanyl) propyl] -3H-imidazo [4,5-b] pyridin-5-yl} pyridin-2,6-diamine and
Example 136 4- {2-Methyl-3-[(2R) -2- (phenylsulfanyl) propyl] -3H-imidazo [4,5-b] pyridin-5-yl} pyridin-2,6-diamine General According to Procedure II, starting from Preparation 2a, a mixture of Example 135 and Example 136 was obtained using 2-phenylsulfanylpropan-1-amine as the appropriate amine. The enantiomers were separated on a CHIRALPAK AS-V column using 40:60 EtOH / heptane + 0.05% DEA as the eluent to give Example 135 as the first eluting enantiomer. HRMS (IT-TOF, ESI) m / z: Calculated value for C ₂₁ H ₂₂ N ₆ S 390.1627, found value: 391.1701 [M + H] ⁺ ee> 99.8% (E1). Example 136 was obtained as the second eluting enantiomer. HRMS (IT-TOF, ESI) m / z: Calculated value for C ₂₁ H ₂₂ N ₆ S 390.1627, found value: 391.1711 [M + H] ⁺ ee = 99.4% (E2).

Example 137 4- {3-[(1S, 2R) -2-benzylcyclopropyl] -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl} pyridin-2,6-diamine and
Example 138 4- {3-[(1S, 2S) -2-benzylcyclopropyl] -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl} pyridin-2,6-diamine and
Example 139 4- {3-[(1R, 2R) -2-benzylcyclopropyl] -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl} pyridin-2,6-diamine and
Example 140 4- {3-[(1R, 2S) -2-benzylcyclopropyl] -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl} pyridin-2,6-diamine General According to Procedure II, starting from preparation 2a, using 2-benzylcyclopropanamine as the appropriate amine, a mixture of cis-products ( Example 137 , Example 138 ) and a mixture of trans-products ( implementation) Example 139 and Example 140 ) were obtained. The enantiomers of these mixtures were separated on a CHIRALCEL OD column using 50:50 EtOH / heptane + 0.05% DEA as eluent.
We obtained Example 137 as the first enantiomer to elute the cis-mixture. HRMS (IT-TOF, ESI) m / z: Calculated value for C ₂₂ H ₂₂ N ₆ 370.1906, found value: 371.1966 [M + H] ⁺ ee> 99.8% (E1). Example 138 was obtained as the second eluting enantiomer of the cis-mixture. HRMS (IT-TOF, ESI) m / z: Calculated value for C ₂₂ H ₂₂ N ₆ [M + H] ⁺ 370.1906, found value: 371.1981 ee> 99.8% (E2).
We obtained Example 139 as the first enantiomer to elute the trans-mixture. _{HRMS (IT-TOF, ESI)} m / z: Calcd 370.1906 for _{C 22 H 22 N 6,} ^{Found: 371.1983 [M + H] +} ee = 99.6% (E1). Example 140 was obtained as the second eluting enantiomer of the trans-mixture. HRMS (IT-TOF, ESI) m / z: Calculated value for C ₂₂ H ₂₂ N ₆ 370.1906, found value: 371.1998 [M + H] ⁺ ee = 99.8% (E2).

Example 141 4- {3-[(2S) -2- (2-methoxyphenoxy) propyl] -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl} pyridine-2,6- Diamines and
Example 142 4- {3-[(2R) -2- (2-methoxyphenoxy) propyl] -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl} pyridin-2,6- Diamine Following the general procedure II, starting from Preparation 2a, using 2- (2-methoxyphenoxy) propan-1-amine as the appropriate amine, a mixture of Example 141 and Example 142 was obtained. The enantiomers were separated on a CHIRALPAK AS-H column using 50:50 1-PrOH / heptane + 0.1% DEA as the eluent to give Example 141 as the first eluting enantiomer. HRMS (TOF, ESI) m / z: Calculated value for C ₂₂ H ₂₄ N ₆ O ₂ 404.1961, found value: 405.2041 [M + H] ⁺ . Example 142 was obtained as the second eluting enantiomer. HRMS (TOF, ESI) m / z: Calculated value of C ₂₂ H ₂₄ N ₆ O ₂ 404.1961, found value: 405.2038 [M + H] ⁺

Example 143 4- [2-Methyl-3- (3-phenoxypropyl) -3H-imidazo [4,5-b] pyridin-5-yl] pyridin-2,6-diamine Following general procedure II, preparation 2a Example 143 was obtained starting from and using 3-phenoxypropan-1-amine as the appropriate amine. HRMS (TOF, ESI) m / z: Calculated value of C ₂₁ H ₂₂ N ₆ O 374.1855, measured value: 375.1946 [M + H] ⁺

Example 144 4- (2,3-Dibutyl-3H-imidazo [4,5-b] pyridin-5-yl) pyridin-2,6-diamine According to general procedure II, starting from preparation 2b and the appropriate amine Example 144 was obtained using as the butane-1-amine. HRMS (TOF, ESI) m / z: Calculated value of C ₁₉ H ₂₆ N ₆ 338.2219, measured value: 339.2289 [M + H] ⁺

Example 145 4- (2-Butyl-3-cyclopentyl-3H-imidazo [4,5-b] pyridin-5-yl) pyridin-2,6-diamine According to general procedure II, starting from preparation 2b, Example 145 was obtained using cyclopentanamine as the appropriate amine. HRMS (TOF, ESI) m / z: Calculated value of C ₂₀ H ₂₆ N ₆ 350.2219 Actual value: 351.2270 [M + H] ⁺

Example 146 4- [2-Butyl-3- (2-phenoxyethyl) -3H-imidazo [4,5-b] pyridin-5-yl] pyridin-2,6-diamine Following general procedure II, preparation 2b Starting from, Example 146 was obtained using 2-phenoxyethanamine as the appropriate amine. HRMS (TOF, ESI) m / z: Calculated value of C ₂₃ H ₂₆ N ₆ O 402.2168 Actual value: 403.2235 [M + H] ⁺

Example 147 4- (2-Butyl-3-methyl-3H-imidazo [4,5-b] pyridin-5-yl) pyridin-2,6-diamine According to general procedure II, starting from preparation 2b, Example 147 was obtained using methanamine as the appropriate amine. HRMS (TOF, ESI) m / z: Calculated value of C ₁₆ H ₂₀ N ₆ 296.1749, measured value: 297.1824 [M + H] ⁺

Example 148 4- (3-Butyl-2-methyl-3H-imidazo [4,5-b] pyridin-5-yl) pyridin-2,6-diamine According to general procedure II, starting from preparation 2a, Example 148 was obtained using butan-1-amine as the appropriate amine. HRMS (TOF, ESI) m / z: Calculated value of C ₁₆ H ₂₀ N ₆ 296.1749, measured value: 297.1842 [M + H] ⁺

Example 149 4- {3-[(1R) -1- (2-fluoropyridin-4-yl) ethyl] -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl} pyridine- 2,6-diamine Example 149 was obtained according to General Procedure II, starting from Preparation 2a, using (1R) -1- (2-fluoro-4-pyridyl) ethanamine as the appropriate amine. HRMS (TOF, ESI) m / z: Calculated value of C ₁₉ H ₁₈ N ₇ F 3633.1608, measured value: 364.1647 [M + H] ⁺

Example 150 4- [3- (3-Methoxypropyl) -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl] pyridin-2,6-diamine Following general procedure II, preparation 2a Example 150 was obtained starting from and using 3-methoxypropan-1-amine as the appropriate amine. HRMS (TOF, ESI) m / z: Calculated value of C ₁₆ H ₂₀ N ₆ O 312.1699, measured value: 313.1762 [M + H] ⁺

Example 151 4- [3- (4-Methoxybutyl) -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl] pyridin-2,6-diamine Following general procedure II, preparation 2a Starting from, Example 151 was obtained using 4-methoxybutan-1-amine as the appropriate amine. HRMS (TOF, ESI) m / z: Calculated value of C ₁₇ H ₂₂ N ₆ O 326.1855, actual value: 327.1919 [M + H] ⁺

Example 152 4- {3- [2- (3-methoxyphenyl) ethyl] -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl} pyridin-2,6-diamine General procedure II Example 152 was obtained starting from Preparation 2a using 2- (3-methoxyphenyl) ethanamine as the appropriate amine. HRMS (TOF, ESI) m / z: Calculated value of C ₂₁ H ₂₂ N ₆ O 3744.1855, measured value: 375.1919 [M + H] ⁺

Example 153 4- [2-Methyl-3- (2-phenoxyethyl) -3H-imidazo [4,5-b] pyridin-5-yl] pyridin-2,6-diamine Following general procedure II, preparation 2a Starting from, Example 153 was obtained using 2-phenoxyethanamine as the appropriate amine. _{HRMS (TOF, ESI) m /} z: C 20 H 20 N 6 O Calculated 360.1699, Found: 361.1774. [M + H] ⁺

Example 154 4- (3-Ethyl-2-methyl-3H-imidazo [4,5-b] pyridin-5-yl) pyridin-2,6-diamine According to general procedure II, starting from preparation 2a, Example 154 was obtained using ethanamine as the appropriate amine. HRMS (TOF, ESI) m / z: Calculated value of C ₁₄ H ₁₆ N ₆ 268.1436, measured value: 269.1510 [M + H] ⁺

Example 155 4- [3- (bicyclo [2.2.1] hept-2-yl) -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl] pyridin-2,6- Diamine Example 155 was obtained according to General Procedure II, starting from Preparation 2a, using norbornane-2-amine as the appropriate amine. HRMS (TOF, ESI) m / z: Calculated value of C ₁₉ H ₂₂ N ₆ 334.1906, measured value: 335.1981 [M + H] ⁺

Example 156 4- (3-Cyclopentyl-2-ethyl-3H-imidazo [4,5-b] pyridin-5-yl) pyridin-2,6-diamine According to general procedure II, starting from preparation 2c, Example 156 was obtained using cyclopentanamine as the appropriate amine. HRMS (TOF, ESI) m / z: Calculated value of C ₁₈ H ₂₂ N ₆ 322.1906, measured value: 323.1993 [M + H] ⁺

Example 157 4- (3-Butyl-2-ethyl-3H-imidazo [4,5-b] pyridin-5-yl) pyridin-2,6-diamine According to general procedure II, starting from preparation 2c, Example 157 was obtained using butan-1-amine as the appropriate amine. HRMS (TOF, ESI) m / z: Calculated value of C ₁₇ H ₂₂ N ₆ 310.1906, measured value: 311.1982 [M + H] ⁺

Example 158 4- [3- (2,3-dihydro-1H-inden-2-yl) -2-ethyl-3H-imidazo [4,5-b] pyridin-5-yl] pyridin-2,6- Diamine Example 158 was obtained according to General Procedure II, starting from Preparation 2c, using indan-2-amine as the appropriate amine. HRMS (TOF, ESI) m / z: Calculated value of C ₂₂ H ₂₂ N ₆ 370.1906, measured value: 371.1992 [M + H] ⁺

Example 159 4- (2-Ethyl-3-methyl-3H-imidazo [4,5-b] pyridin-5-yl) pyridin-2,6-diamine According to general procedure II, starting from preparation 2c, Example 159 was obtained using methanamine as the appropriate amine. HRMS (TOF, ESI) m / z: Calculated value of C ₁₄ H ₁₆ N ₆ 268.1436, measured value: 269.1512 [M + H] ⁺

Example 160 4- (3-Cyclopentyl-2-propyl-3H-imidazo [4,5-b] pyridin-5-yl) pyridin-2,6-diamine According to general procedure II, starting from preparation 2d, Example 160 was obtained using cyclopentanamine as the appropriate amine. HRMS (TOF, ESI) m / z: Calculated value of C ₁₉ H ₂₄ N ₆ 336.0206 Actual value: 337.2150 [M + H] ⁺

Example 161 4- (3-Butyl-2-propyl-3H-imidazo [4,5-b] pyridin-5-yl) pyridin-2,6-diamine According to general procedure II, starting from preparation 2d, Example 161 was obtained using butan-1-amine as the appropriate amine. HRMS (TOF, ESI) m / z: Calculated value of C ₁₈ H ₂₄ N ₆ 324.2062, found value: 325.2145 [M + H] ⁺

Example 162 4- [3- (2-Phenoxyethyl) -2-propyl-3H-imidazo [4,5-b] pyridin-5-yl] pyridin-2,6-diamine Preparation 2d according to general procedure II Starting from, Example 162 was obtained using 2-phenoxyethanamine as the appropriate amine. HRMS (IT-TOF, ESI) m / z: Calculated value of C ₂₂ H ₂₄ N ₆ O 388.2012 Actual value: 389.2081 [M + H] ⁺

Example 163 4- (3-Methyl-2-propyl-3H-imidazo [4,5-b] pyridin-5-yl) pyridin-2,6-diamine According to general procedure II, starting from preparation 2d, Example 163 was obtained using methanamine as the appropriate amine. HRMS (TOF, ESI) m / z: Calculated value of C ₁₅ H ₁₈ N ₆ 282.1593, measured value: 283.1663 [M + H] ⁺

Example 164 4- (3- {2-[(5-chloropyridin-2-yl) oxy] ethyl} -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl) pyridine-2 , 6-diamine Following Example III, starting from Preparation 3a, using Example 2 with 2-fluoro-5-chloropyridine as the appropriate aryl halide. HRMS (IT-TOF, ESI) m / z: Calculated value of C ₁₉ H ₁₈ N ₇ OCl 395.1261, measured value: 396.1326 [M + H] ⁺

Example 165 4- (3- {2-[(6-chloropyridin-2-yl) oxy] ethyl} -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl) pyridine-2 , 6-diamine Following Example III, starting from Preparation 3a, using 2-fluoro-6-chloropyridine as the appropriate aryl halide, gave Example 165 . HRMS (IT-TOF, ESI) m / z: Calculated value of C ₁₉ H ₁₈ N ₇ OCl 395.1261, found value: 396.1331. [M + H] ⁺

Example 166 4- (3- {2-[(3-chloropyridin-2-yl) oxy] ethyl} -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl) pyridine-2 , 6-diamine Following Example III, starting from Preparation 3a, using 2-fluoro-3-chloropyridine as the appropriate aryl halide, gave Example 166 . HRMS (IT-TOF, ESI) m / z: Calculated value of C ₁₉ H ₁₈ N ₇ OCl 395.1261, measured value: 396.1319 [M + H] ⁺

Example 167 4- (3- {2-[(6-Fluoropyridin-2-yl) oxy] ethyl} -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl) pyridin-2 , 6-diamine Following Example III, starting from Preparation 3a, using 2,6-difluoropyridine as the appropriate aryl halide, gave Example 167 . HRMS (TOF, ESI) m / z: Calculated value of C ₁₉ H ₁₈ N ₇ OF 379.1557, measured value: 380.1635 [M + H] ⁺

Example 168 4- (3- {2-[(6-Bromopyridin-2-yl) oxy] ethyl} -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl) pyridin-2 , 6-diamine Following Example III, starting from Preparation 3a, using 2-fluoro-6-bromopyridine as the appropriate aryl halide, gave Example 168 . HRMS (IT-TOF, ESI) m / z: Calculated value of C ₁₉ H ₁₈ N ₇ OBr 439.0756, actual value: 440.0823 [M + H] ⁺

Example 169 4- (3- {2-[(3-bromopyridin-2-yl) oxy] ethyl} -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl) pyridin-2 , 6-diamine Following Example III, starting from Preparation 3a, using 2-fluoro-3-bromopyridine as the appropriate aryl halide, gave Example 169 . HRMS (IT-TOF, ESI) m / z: Calculated value of C ₁₉ H ₁₈ N ₇ OBr 439.0756, actual value: 440.0817 [M + H] ⁺

Example 170 4- (3- {2-[(5-bromopyridin-2-yl) oxy] ethyl} -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl) pyridine-2 , 6-diamine Example 170 was obtained according to general procedure III, starting from preparation 3a, using 2-fluoro-5-bromopyridine as the appropriate aryl halide. HRMS (IT-TOF, ESI) m / z: Calculated value of C ₁₉ H ₁₈ N ₇ OBr 439.0756, actual value: 440.0811 [M + H] ⁺

Example 171 4- (3- {2-[(5-fluoropyridin-2-yl) oxy] ethyl} -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl) pyridine-2 , 6-diamine Following Example III, starting from Preparation 3a, using 2,5-difluoropyridine as the appropriate aryl halide, gave Example 171 . HRMS (IT-TOF, ESI) m / z: Calculated value of C ₁₉ H ₁₈ N ₇ OF 379.557, measured value: 380.1617 [M + H] ⁺

Example 172 4- [3- (2-{[6- (fluoromethyl) pyridin-2-yl] oxy} ethyl) -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl] Pyridine-2,6-diamine Example 172 was obtained according to General Procedure III, starting from Preparation 3a, using 2-fluoro-6-fluoromethylpyridine as the appropriate aryl halide. HRMS (TOF, ESI) m / z: Calculated value of C ₂₀ H ₂₀ FN ₇ O 393.713, measured value: 394.784 [M + H] ⁺

Example 173 4- [3- (2-{[6- (difluoromethyl) pyridin-2-yl] oxy} ethyl) -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl] Pyridine-2,6-diamine Example 173 was obtained according to General Procedure III, starting from Preparation 3a, using 2-fluoro-6-difluoromethylpyridine as the appropriate aryl halide. HRMS (TOF, ESI) m / z: Calculated value of C ₂₀ H ₁₉ F ₂ N ₇ O 411.1619, measured value: 412.1686 [M + H] ⁺

Example 174 4- {2-methyl-3-[(2S) -2- (pyridin-2-yloxy) propyl] -3H-imidazo [4,5-b] pyridin-5-yl} pyridine-2,6 -Diamines and
Example 175 4- {2-methyl-3-[(2R) -2- (pyridin-2-yloxy) propyl] -3H-imidazo [4,5-b] pyridin-5-yl} pyridine-2,6 -Diamine Following the general procedure III, starting from Preparation 3b, using 2-fluoropyridine as the appropriate aryl halide, gave a mixture of Example 174 and Example 175 . The enantiomers were separated on a CHIRALCEL OK column using 50:50 EtOH / heptane + 0.05% DEA as the eluent to give Example 174 as the first eluting enantiomer. HRMS (IT-TOF, ESI) m / z: Calculated value for C ₂₀ H ₂₁ N ₇ O 375.1808, found value: 376.1867 [M + H] ⁺ ee> 99.8% (E1). Example 175 was obtained as the second eluting enantiomer. HRMS (IT-TOF, ESI) m / z: Calculated value for C ₂₀ H ₂₁ N ₇ O 375.1808, found value: 376.1872 [M + H] ⁺ ee> 99.8% (E2).

Example 176 4- (3-{(2S) -2-[(6-chloropyridin-2-yl) oxy] propyl} -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl ) Pyridine-2,6-diamine and
Example 177 4- (3-{(2R) -2-[(6-chloropyridin-2-yl) oxy] propyl} -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl ) Pyridine-2,6-diamine Following procedure III, starting from Preparation 3b, using 2-fluoro-6-chloropyridine as the appropriate aryl halide, gives a mixture of Example 176 and Example 177. It was. The enantiomers were separated on an OJ column using EtOH + 0.05% DEA as the eluent to give Example 176 as the first eluting enantiomer. _{HRMS (IT-TOF, ESI)} m / z: C 20 H 20 N 7 Calculated OCl 409.1418, ^{Found: 410.1469 [M + H] +} ee> 99.8% (E1). Example 177 was obtained as an enantiomer that elutes later. HRMS (IT-TOF, ESI) m / z: Calculated value of C ₂₀ H ₂₀ N ₇ OCl 409.1418, actual value: 410.1482 [M + H] ⁺ ee = 98.8% (E2)

Example 178 4- (3-{(2S) -2-[(5-fluoropyridin-2-yl) oxy] propyl} -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl ) Pyridine-2,6-diamine and
Example 179 4- (3-{(2R) -2-[(5-fluoropyridin-2-yl) oxy] propyl} -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl ) Pyridine-2,6-diamine Following general procedure III, starting from Preparation 3b, using 2,5-difluoropyridine as the appropriate aryl halide, gave a mixture of Example 178 and Example 179 . The enantiomers were separated on an AS column using 50:50 1-PrOH / heptane + 0.1% DEA as the eluent to give Example 178 as the first eluting enantiomer. _{HRMS (IT-TOF, ESI)} m / z: C 20 H 20 N 7 O Calculated 393.1713, ^{Found: 394.1780 [M + H] +} ee = 99.4% (E1). Example 179 was obtained as an enantiomer that elutes later. _{HRMS (IT-TOF, ESI)} m / z: C 20 H 20 N 7 O Calculated 393.1713, ^{Found: 394.1774 [M + H] +} ee = 98.6% (E2).

Example 180 4- (3-{(2S) -2-[(6-bromopyridin-2-yl) oxy] propyl} -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl ) Pyridine-2,6-diamine and
Example 181 4- (3-{(2R) -2-[(6-bromopyridin-2-yl) oxy] propyl} -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl ) Pyridine-2,6-diamine Following procedure III, starting from Preparation 3b, using 2-fluoro-6-bromopyridine as the appropriate aryl halide, gives a mixture of Example 180 and Example 181. It was. The enantiomers were separated on a CHIRALPAK AS-H column using 40:60 EtOH / heptane + 0.1% DEA as the eluent to give Example 180 as the first eluting enantiomer. HRMS (IT-TOF, ESI) m / z: Calculated value of C ₂₀ H ₂₀ N ₇ OBr 453.0913, found value: 454.970 [M + H] ⁺ ee> 99.8% (E1). Example 181 was obtained as an enantiomer that elutes later. _{HRMS (IT-TOF, ESI)} m / z: C 20 H 20 N 7 Calculated OBr 453.0913, ^{Found: 454.0967 [M + H] +} ee = 99.0% (E2).

Example 182 4- (3-{(2S) -2-[(3-bromopyridin-2-yl) oxy] propyl} -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl ) Pyridine-2,6-diamine and
Example 183 4- (3-{(2R) -2-[(3-bromopyridin-2-yl) oxy] propyl} -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl ) Pyridine-2,6-diamine Following procedure III, starting from Preparation 3b, using 2-fluoro-3-bromopyridine as the appropriate aryl halide, gives a mixture of Example 182 and Example 183. It was. The enantiomers were separated on a CHIRALPAK AS-H column using 70:30 2-PrOH / heptane + 0.1% DEA as the eluent to give Example 182 as the first eluting enantiomer. _{HRMS (IT-TOF, ESI)} m / z: C 20 H 20 N 7 Calculated OBr 453.0913, ^{Found: 454.0963 [M + H] +} ee> 99.8% (E1). Example 183 was obtained as an enantiomer that elutes later. _{HRMS (IT-TOF, ESI)} m / z: C 20 H 20 N 7 Calculated OBr 453.0913, ^{Found: 454.0968 [M + H] +} ee = 99.0% (E2).

Example 184 4- (3-{(2S) -2-[(5-chloropyridin-2-yl) oxy] propyl} -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl ) Pyridine-2,6-diamine and
Example 185 4- (3-{(2R) -2-[(5-chloropyridin-2-yl) oxy] propyl} -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl ) Pyridine-2,6-diamine According to general procedure III, starting from Preparation 3b, using 2-fluoro-5-chloropyridine as the appropriate aryl halide, a mixture of Example 184 and Example 185 is obtained. It was. The enantiomers were separated on an OJ column using 50:50 EtOH / heptane + 0.05% DEA as the eluent to give Example 184 as the first eluting enantiomer. _{HRMS (IT-TOF, ESI)} m / z: C 20 H 20 N 7 OCl Calculated 409.1418, Found: 410.1469. [M + H] ⁺ ee> 99.8% (E1). Example 185 was obtained as an enantiomer that elutes later. _{HRMS (TOF, ESI) m /} z: C 20 H 20 ClN 7 O Calculated 409.1418, ^{Found: 410.1471 [M + H] +} ee99.8% (E2).

Example 186 4- (3-{(2S) -2-[(5-bromopyridin-2-yl) oxy] propyl} -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl ) Pyridine-2,6-diamine and
Example 187 4- (3-{(2R) -2-[(5-bromopyridin-2-yl) oxy] propyl} -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl ) Pyridine-2,6-diamine Following general procedure III, starting from Preparation 3b, using 2-fluoro-5-bromopyridine as the appropriate aryl halide, gives a mixture of Example 186 and Example 187. It was. The enantiomers were separated on an OJ column using 60:40 EtOH / heptane + 0.05% DEA as the eluent to give Example 186 as the first eluting enantiomer. _{HRMS (IT-TOF, ESI)} m / z: C 20 H 20 N 7 OBr Calculated 453.0913 ^{Found: 454.0967 [M + H] +} ee> 99.8% (E1). Example 187 was obtained as an enantiomer that elutes later. _{HRMS (IT-TOF, ESI)} m / z: C 20 H 20 N 7 OBr Calculated 453.0913 ^{Found: 454.0983 [M + H] +} ee = 99.2% (E2).

Example 188 4- (3-{(2S) -2-[(6-fluoropyridin-2-yl) oxy] propyl} -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl ) Pyridine-2,6-diamine and
Example 189 4- (3-{(2R) -2-[(6-fluoropyridin-2-yl) oxy] propyl} -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl ) Pyridine-2,6-diamine According to general procedure III, starting from Preparation 3b, using 2,6-difluoropyridine as the appropriate aryl halide, a mixture of Example 188 and Example 189 was obtained. The enantiomers were separated on a CHIRALCEL OJ-H column using EtOH + 0.1% DEA as the eluent to give Example 188 as the first eluting enantiomer. _{HRMS (IT-TOF, ESI)} m / z: C 20 H 20 N 7 OF Calculated 393.1713, ^{Found: 394.1779 [M + H] +} ee> 99.8% (E1). Example 189 was obtained as an enantiomer that elutes later. _{HRMS (IT-TOF, ESI)} m / z: C 20 H 20 N 7 OF Calculated 393.1713, ^{Found: 394.1773 [M + H] +} ee = 99.6% (E2).

Example 190 4- (3-{(2S) -2-[(3-chloropyridin-2-yl) oxy] propyl} -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl ) Pyridine-2,6-diamine and
Example 191 4- (3-{(2R) -2-[(3-chloropyridin-2-yl) oxy] propyl} -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl ) Pyridine-2,6-diamine Following procedure III, starting from Preparation 3b, using 2-fluoro-3-chloropyridine as the appropriate aryl halide, gives a mixture of Example 190 and Example 191. It was. The enantiomers were separated on a CHIRALPAK AS-V column using 70:30 2-PrOH / heptane + 0.05% DEA as the eluent to give Example 190 as the first eluting enantiomer. _{HRMS (IT-TOF, ESI)} m / z: C 20 H 20 N 7 Calculated OCl 409.1418, ^{Found: 410.1477 [M + H] +} ee> 99.8% (E1). Example 191 was obtained as an enantiomer that elutes later. HRMS (IT-TOF, ESI) m / z: Calculated value of C ₂₀ H ₂₀ N ₇ OCl 409.1418, actual value: 410.1492 [M + H] ⁺ ee> 99.8% (E2)

Example 192 4- (3-{(2S) -2-[(3,6-difluoropyridin-2-yl) oxy] propyl} -2-methyl-3H-imidazo [4,5-b] pyridine-5 -Yl) pyridine-2,6-diamine and
Example 193 4- (3-{(2R) -2-[(3,6-difluoropyridin-2-yl) oxy] propyl} -2-methyl-3H-imidazo [4,5-b] pyridine-5 -Yl) pyridine-2,6-diamine Following general procedure III, starting from Preparation 3b, using 2,3,6-trifluoropyridine as the appropriate aryl halide, of Example 192 and Example 193 A mixture was obtained. The enantiomers were separated on a CHIRALCEL OK column using 60:40 EtOH / heptane + 0.05% DEA as the eluent to give Example 192 as the first eluting enantiomer. HRMS (TOF, ESI) m / z: Calculated value of C ₂₀ H ₁₉ F ₂ N ₇ O 411.1699, found value: 412.1694 [M + H] ⁺ ee> 99.8% (E1). Example 193 was obtained as an enantiomer eluting later. HRMS (TOF, ESI) m / z: Calculated value for C ₂₀ H ₁₉ F ₂ N ₇ O 411.1619, found value: 412.1700 [M + H] ⁺ ee> 99.8% (E2).

Example 194 4- [2-Methyl-3- (2-{[6- (trifluoromethyl) pyridin-2-yl] oxy} ethyl) -3H-imidazo [4,5-b] pyridin-5-yl Pyridine-2,6-diamine Example 194 was obtained according to General Procedure IV, starting from Preparation 3a, using 6-trifluoromethyl-2-pyridone as the appropriate phenol analog. HRMS (IT-TOF, ESI) m / z: Calculated value of C ₂₀ H ₁₈ N ₇ OF ₃ 429.1525, measured value: 430.1608 [M + H] ⁺

Example 195 4- (2-methyl-3- {2-[(6-methylpyridin-2-yl) oxy] ethyl} -3H-imidazo [4,5-b] pyridin-5-yl) pyridine-2 , 6-diamine Following Example IV, starting from Preparation 3a, using Example 6 195 using 6-methyl-2-pyridone as the appropriate phenol analog. HRMS (TOF, ESI) m / z: Calculated value of C ₂₀ H ₂₁ N ₇ O 375.1808, measured value: 376.1872 [M + H] ⁺

Example 196 4- (3- {2-[(6-Aminopyridin-2-yl) oxy] ethyl} -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl) pyridine-2 , 6-diamine Example 196 was obtained according to General Procedure IV, starting from Preparation 3a, using 6-amino-2-pyridone as the appropriate phenol analog. HRMS (IT-TOF, ESI) m / z: Calculated value of C ₁₉ H ₂₀ N ₈ O 376.1760, measured value: 377.1826 [M + H] ⁺

Example 197 6- {2- [5- (2,6-diaminopyridin-4-yl) -2-methyl-3H-imidazo [4,5-b] pyridin-3-yl] ethoxy} pyridine-2- Carbonitrile Example 197 was obtained according to General Procedure IV, starting from Preparation 3a, using 6-cyano-2-pyridone as the appropriate phenol analog. HRMS (IT-TOF, ESI) m / z: Calculated value of C ₂₀ H ₁₈ N ₈ O 3866.1604, measured value: 387.1655 [M + H] ⁺

Example 198 4- {3- [2- (4-Fluorophenoxy) ethyl] -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl} pyridin-2,6-diamine General procedure IV Example 198 was obtained starting from Preparation 3a using 4-fluorophenol as the appropriate phenol analog. HRMS (TOF, ESI) m / z: Calculated value of C ₂₀ H ₁₉ N ₆ OF 378.1604, measured value: 379.1683 [M + H] ⁺

Example 199 4- {3- [2- (3-Fluorophenoxy) ethyl] -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl} pyridin-2,6-diamine General Procedure IV Example 199 was obtained starting from Preparation 3a using 3-fluorophenol as the appropriate phenol analog. HRMS (TOF, ESI) m / z: Calculated value of C ₂₀ H ₁₉ N ₆ OF 378.1604, measured value: 379.1621 [M + H] ⁺

Example 200 4- {3- [2- (3-Chlorophenoxy) ethyl] -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl} pyridin-2,6-diamine General procedure IV Example 200 was obtained starting from Preparation 3a using 3-chlorophenol as the appropriate phenol analog. HRMS (TOF, ESI) m / z: Calculated value of C ₂₀ H ₁₉ N ₆ OCl 394.1309, actual value: 395.1308 [M + H] ⁺

Example 201 4- {2-Methyl-3- [2- (3-methylphenoxy) ethyl] -3H-imidazo [4,5-b] pyridin-5-yl} pyridin-2,6-diamine General procedure IV Example 201 was obtained starting from Preparation 3a using 3-methylphenol as the appropriate phenol analog. HRMS (TOF, ESI) m / z: Calculated value of C ₂₁ H ₂₂ N ₆ O 374.1855, measured value: 375.1908 [M + H] ⁺

Example 202 4- {3- [2- (3-methoxyphenoxy) ethyl] -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl} pyridin-2,6-diamine General procedure IV Example 202 was obtained starting from Preparation 3a using 3-methoxyphenol as the appropriate phenol analog. HRMS (TOF, ESI) m / z: Calculated value of C ₂₁ H ₂₂ N ₆ O ₂ 390.1804, measured value: 391.1810 [M + H] ⁺

Example 203 4- {3- [2- (2-Fluorophenoxy) ethyl] -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl} pyridin-2,6-diamine General procedure IV Example 203 was obtained starting from Preparation 3a using 2-fluorophenol as the appropriate phenol analog. HRMS (TOF, ESI) m / z: Calculated value of C ₂₀ H ₁₉ N ₆ OF 378.1604, measured value: 379.1485 [M + H] ⁺

Example 204 4- {3- [2- (2-Chlorophenoxy) ethyl] -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl} pyridin-2,6-diamine General procedure IV Example 204 was obtained starting from Preparation 3a using 2-chlorophenol as the appropriate phenol analog. HRMS (TOF, ESI) m / z: Calculated value of C ₂₀ H ₁₉ N ₆ OCl 394.1309, measured value: 395.1387 [M + H] ⁺

Example 205 4- {2-Methyl-3- [2- (2-methylphenoxy) ethyl] -3H-imidazo [4,5-b] pyridin-5-yl} pyridin-2,6-diamine General procedure IV Example 205 was obtained starting from preparation 3a using 2-methylphenol as the appropriate phenol analog. HRMS (TOF, ESI) m / z: Calculated value of C ₂₁ H ₂₂ N ₆ O 3744.1855, measured value: 375.1929 [M + H] ⁺

Example 206 4- {3- [2- (2-methoxyphenoxy) ethyl] -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl} pyridin-2,6-diamine General procedure IV Example 206 was obtained starting from Preparation 3a using 2-methoxyphenol as the appropriate phenol analog. HRMS (TOF, ESI) m / z: Calculated value of C ₂₁ H ₂₂ N ₆ O ₂ 390.1804, measured value: 391.1888 [M + H] ⁺

Example 207 4- {3- [2- (4-chlorophenoxy) ethyl] -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl} pyridin-2,6-diamine General procedure IV Example 207 was obtained starting from Preparation 3a using 4-chlorophenol as the appropriate phenol analog. HRMS (TOF, ESI) m / z: Calculated value of C ₂₀ H ₁₉ N ₆ OCl 394.1309, found value: 395.1389 [M + H] ⁺

Example 208 4- {2-Methyl-3- [2- (4-methylphenoxy) ethyl] -3H-imidazo [4,5-b] pyridin-5-yl} pyridin-2,6-diamine General procedure IV Example 208 was obtained starting from Preparation 3a using 4-methylphenol as the appropriate phenol analog. HRMS (TOF, ESI) m / z: Calculated value of C ₂₁ H ₂₂ N ₆ O 3744.1855, measured value: 375.1937 [M + H] ⁺

Example 209 4- {3- [2- (4-methoxyphenoxy) ethyl] -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl} pyridin-2,6-diamine General procedure IV Example 209 was obtained starting from Preparation 3a using 4-methoxyphenol as the appropriate phenol analog. HRMS (TOF, ESI) m / z: Calculated value of C ₂₁ H ₂₂ N ₆ O ₂ 390.1804, measured value: 391.1883 [M + H] ⁺

Example 210 4- {3- [2- (1H-Indol-5-yloxy) ethyl] -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl} pyridin-2,6-diamine Example 210 was obtained according to General Procedure IV, starting from Preparation 3a, using 1H-indole-5-ol as the appropriate phenol analog. HRMS (TOF, ESI) m / z: Calculated value of C ₂₂ H ₂₁ N ₇ O 399.1808, measured value: 400.1848 [M + H] ⁺

Example 211 4- {3- [2- (2-methoxy-5-methylphenoxy) ethyl] -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl} pyridin-2,6- Diamine Example 211 was obtained according to General Procedure IV, starting from Preparation 3a, using 2-methoxy-5-methylphenol as the appropriate phenol analog. HRMS (TOF, ESI) m / z: Calculated value of C ₂₂ H ₂₄ N ₆ O ₂ 404.1961, measured value: 405.2202 [M + H] ⁺

Example 212 4- {3- [2- (2,6-difluorophenoxy) ethyl] -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl} pyridin-2,6-diamine General Example 212 was obtained according to Procedure IV, starting from Preparation 3a, using 2,6-difluorophenol as the appropriate phenol analog. HRMS (TOF, ESI) m / z: Calculated value of C ₂₀ H ₁₈ N ₆ OF ₂ 396.1510, measured value: 397.1570 [M + H] ⁺

Example 213 4- {3- [2- (2,6-dimethoxyphenoxy) ethyl] -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl} pyridin-2,6-diamine General Example 213 was obtained according to Procedure IV, starting from Preparation 3a, using 2,6-dimethoxyphenol as the appropriate phenol analog. HRMS (TOF, ESI) m / z: Calculated value of C ₂₂ H ₂₄ N ₆ O ₃ 420.1910, measured value: 421.1979 [M + H] ⁺

Example 214 4- (2-methyl-3- {2- [2- (propan-2-yloxy) phenoxy] ethyl} -3H-imidazo [4,5-b] pyridin-5-yl) pyridine-2, 6-diamine Example 214 was obtained according to General Procedure IV, starting from Preparation 3a, using 2-isopropoxyphenol as the appropriate phenol analog. HRMS (TOF, ESI) m / z: Calculated value of C ₂₃ H ₂₆ N ₆ O ₂ 418.2117, actual value: 419.2195 [M + H] ⁺

Example 215 4- {3- [2- (2-Ethoxyphenoxy) ethyl] -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl} pyridin-2,6-diamine General procedure IV The Example 215 was obtained starting from Preparation 3a using 2-ethoxyphenol as the appropriate phenol analog. HRMS (TOF, ESI) m / z: Calculated value of C ₂₂ H ₂₄ N ₆ O ₂ 404.1961, measured value: 405.2030 [M + H] ⁺

Example 216 4- {2-Methyl-3- [2- (pyridin-3-yloxy) ethyl] -3H-imidazo [4,5-b] pyridin-5-yl} pyridin-2,6-diamine General procedure Following Example IV, starting from Preparation 3a, Example 216 was obtained using 3-hydroxypyridine as the appropriate phenol analog. HRMS (TOF, ESI) m / z: Calculated value of C ₁₉ H ₁₉ N ₇ O 361.1651, measured value: 362.1724 [M + H] ⁺

Example 217 4- {2-Methyl-3- [2- (pyridin-2-yloxy) ethyl] -3H-imidazo [4,5-b] pyridin-5-yl} pyridin-2,6-diamine General procedure Following Example IV, starting from Preparation 3a, Example 217 was obtained using 2-pyridone as the appropriate phenol analog. HRMS (TOF, ESI) m / z: Calculated value of C ₁₉ H ₁₉ N ₇ O 361.1651, measured value: 362.1731 [M + H] ⁺

Example 218 4- (2-methyl-3- {2-[(1-methyl-1H-pyrazol-5-yl) oxy] ethyl} -3H-imidazo [4,5-b] pyridin-5-yl) Pyridine-2,6-diamine Example 218 was obtained according to general procedure IV, starting from Preparation 3a, using 1-methyl-1H-pyrazol-5-ol as the appropriate phenol analog. HRMS (TOF, ESI) m / z: Calculated value of C ₁₈ H ₂₀ N ₈ O 3644.1760, measured value: 3655.1822 [M + H] ⁺

Example 219 4- {2-Methyl-3- [2- (pyrimidin-2-yloxy) ethyl] -3H-imidazo [4,5-b] pyridin-5-yl} pyridin-2,6-diamine General procedure Example 219 was obtained according to IV, starting from Preparation 3a, using pyrimidin-2 (1H) -one as the appropriate phenol analog. HRMS (TOF, ESI) m / z: Calculated value of C ₁₈ H ₁₈ N ₈ O 362.1604, measured value: 363.1675 [M + H] ⁺

Example 220 4- (2-Chloro-3-cyclopentyl-3H-imidazo [4,5-b] pyridin-5-yl) pyridine-2,6-diamine Following general procedure V, cyclopentanamine as the appropriate amine Step 220 was omitted and Example 220 was obtained. HRMS (TOF, ESI) m / z: Calculated value of C ₁₆ H ₁₇ N ₆ Cl 328.1203, found value: 329.1272 [M + H] ⁺

Example 221 3-Cyclopentyl-5- (2,6-diaminopyridin-4-yl) -3H-imidazo [4,5-b] pyridine-2-carbonitrile Following general procedure V, cyclopentanamine as the appropriate amine Example 221 was obtained using HRMS (TOF, ESI) m / z: Calculated value of C ₁₇ H ₁₇ N ₇ 319.1545, measured value: 320.1623 [M + H] ⁺

Example 222 5- (2,6-diaminopyridin-4-yl) -3- (2-phenoxyethyl) -3H-imidazo [4,5-b] pyridine-2-carbonitrile According to general procedure V Example 222 was obtained using 2-phenoxyethanamine as the amine. HRMS (TOF, ESI) m / z: Calculated value of C ₂₀ H ₁₇ N ₇ O 371.1495, measured value: 372.1575 [M + H] ⁺

Example 223 5- (2,6-diaminopyridin-4-yl) -3-ethyl-3H-imidazo [4,5-b] pyridine-2-carbonitrile According to general procedure V, using ethanamine as the appropriate amine Example 223 was obtained. HRMS (IT-TOF, ESI) m / z: Calculated value of C ₁₄ H ₁₃ N ₇ 279.1232, measured value: 280.1315 [M + H] ⁺

Example 224 3-Cyclopropyl-5- (2,6-diaminopyridin-4-yl) -3H-imidazo [4,5-b] pyridine-2-carbonitrile Following general procedure V, cyclopropane as the appropriate amine Example 224 was obtained using an amine. HRMS (IT-TOF, ESI) m / z: Calculated value of C ₁₅ H ₁₃ N ₇ 291.1232, measured value: 292.1303 [M + H] ⁺

Example 225 5- (2,6-diaminopyridin-4-yl) -3- (prop-2-en-1-yl) -3H-imidazo [4,5-b] pyridine-2-carbonitrile General procedure Example 225 was obtained according to V, using prop-2-en-1-amine as the appropriate amine. HRMS (IT-TOF, ESI) m / z: Calculated value of C ₁₅ H ₁₃ N ₇ 291.1232, measured value: 292.1300 [M + H] ⁺

Example 226 5- (2,6-diaminopyridin-4-yl) -3- (4,4,4-trifluorobutyl) -3H-imidazo [4,5-b] pyridine-2-carbonitrile General procedure Example 226 was obtained according to V, using 4,4,4-trifluorobutan-1-amine as the appropriate amine. HRMS (IT-TOF, ESI) m / z: Calculated value of C ₁₆ H ₁₄ N ₇ F ₃ 361.1263, measured value: 362.1338 [M + H] ⁺

Example 227 5- (2,6-diaminopyridin-4-yl) -3-methyl-3H-imidazo [4,5-b] pyridine-2-carbonitrile According to general procedure V, using methanamine as the appropriate amine Example 227 was obtained. HRMS (IT-TOF, ESI) m / z: Calculated value of C ₁₃ H ₁₁ N ₇ 265.1076, measured value: 266.1139 [M + H] ⁺

Example 228 4- [2- (Difluoromethyl) -3-methyl-3H-imidazo [4,5-b] pyridin-5-yl] pyridin-2,6-diamine Starting from Preparation 4 according to general procedure VI Example 228 was then obtained using ethyl difluoroacetate as the appropriate acetic acid derivative. HRMS (TOF, ESI) m / z: Calculated value of C ₁₃ H ₁₂ N ₆ F ₂ 290.10092, measured value: 291.1161 [M + H] ⁺

Example 229 4- [3-Methyl-2- (trifluoromethyl) -3H-imidazo [4,5-b] pyridin-5-yl] pyridin-2,6-diamine From Preparation 4 according to general procedure VI Starting, Example 229 was obtained using trifluoroacetic acid as the appropriate acetic acid derivative. _{HRMS (TOF, ESI) m /} z: C 13 H 11 N 6 F 3 Calculated 308.0997, Found: 309.1078 [M ^{+ H]} +

Example 230 N- [6-Amino-4- (3-butyl-2-methyl-3H-imidazo [4,5-b] pyridin-5-yl) pyridin-2-yl] -2-phenoxyacetamide 4- (3-Butyl-2-methyl-imidazo [4,5-b] pyridin-5-yl) -N ² -triphenylmethyl-pyridine-2,6-diamine ( Preparation 5 ) 200 mg (0.37 mmol, 1 Eq) and triethylamine in a solution of 155 μL (1.11 mmol, 3 eq) in dry THF (4 mL) was added 41 μL of 2-chloroacetyl chloride (0.51 mmol, 1.4 eq) and the mixture was observed for further conversion. Stir until no more. Volatiles were removed under reduced pressure and the residue was dissolved in dry DMF (5 mL), then 70 mg (0.74 mmol, 2 eq) phenol and 154 mg (1.11 mmol, 3 eq) potassium carbonate were added. . The resulting mixture was stirred until no further conversion was observed. It was diluted with brine and extracted with DCM. The combined organic phases were dried over MgSO ₄ , filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography on a silica column initially using DCM / MeOH (1.2% NH ₃ ) as eluent during which the trityl group was also removed, followed by 5 mM NH ₄ as eluent. Purification by preparative reverse phase chromatography using aqueous HCO ₃ and MeCN gave Example 230 . HRMS (TOF, ESI) m / z: Calculated value of C ₂₄ H ₂₆ N ₆ O ₂ 430.2117, measured value: 431.2195 [M + H] ⁺

Example 231 N-benzyl-4- (3-butyl-2-methyl-3H-imidazo [4,5-b] pyridin-5-yl) pyridine-2,6-diamine 4- (3-butyl-2- methyl - imidazo [4,5-b] pyridin-5-yl) -N ² - triphenylmethyl - pyridine-2,6-diamine (preparation 5) 269 mg (0.5 mmol, 1 eq) and benzaldehyde 159 mg (1 To a solution of .5 mmol, 3 eq) in DMF / MeOH (3/2 mL) was added 113 mg (3 mmol, 6 eq) sodium borohydride in small portions. The resulting mixture was stirred at 60 ° C. in the presence of acetic acid (100 μL) until no further conversion was observed. The pH was set to 5 with 2M aqueous HCl and the resulting mixture was stirred until no further conversion (detritylation) was observed. The mixture was neutralized with 10% aqueous K ₂ CO ₃ solution, diluted with brine and extracted with DCM. The combined organic phases were dried over MgSO ₄ , filtered and the filtrate was concentrated under reduced pressure. The crude product was purified via preparative reverse phase chromatography using 5 mM aqueous NH ₄ HCO ₃ and MeCN as eluents to give Example 231 . HRMS (TOF, ESI) m / z: Calculated value of C ₂₃ H ₂₆ N ₆ 386.2219, measured value: 387.2295 [M + H] ⁺

Example 232 N- [6-Amino-4- (3-butyl-2-methyl-3H-imidazo [4,5-b] pyridin-5-yl) pyridin-2-yl] -2-cyclohexylacetamide General procedure Example 232 was obtained according to VII, starting from Example 148 , using cyclohexylacetyl chloride as the appropriate acid chloride. HRMS (TOF, ESI) m / z: Calculated value of C ₂₄ H ₃₂ N ₆ O 420.2638, measured value: 421.2719 [M + H] ⁺

Example 233 N- [6-Amino-4- (3-butyl-2-methyl-3H-imidazo [4,5-b] pyridin-5-yl) pyridin-2-yl] -2-chlorobenzamide General procedure Example 233 was obtained according to VII starting from Example 148 using 2-chlorobenzoyl chloride as the appropriate acid chloride. HRMS (TOF, ESI) m / z: Calculated value of C ₂₃ H ₂₃ N ₆ OCl 434.1622, actual value: 435.1702 [M + H] ⁺

Example 234 N- [6-Amino-4- (3-butyl-2-methyl-3H-imidazo [4,5-b] pyridin-5-yl) pyridin-2-yl] cyclohexanecarboxamide Following general procedure VII Starting from Example 148 , Example 234 was obtained using cyclohexanoyl chloride as the appropriate acid chloride. HRMS (TOF, ESI) m / z: Calculated value of C ₂₃ H ₃₀ N ₆ O 406.2481, found value: 407.2557 [M + H] ⁺

Example 235 N- [6-Amino-4- (3-butyl-2-methyl-3H-imidazo [4,5-b] pyridin-5-yl) pyridin-2-yl] -2-phenylacetamide General procedure Example 235 was obtained according to VII, starting from Example 148 and using phenylacetyl chloride as the appropriate acid chloride. HRMS (TOF, ESI) m / z: Calculated value of C ₂₄ H ₂₆ N ₆ O 414.2168, measured value: 415.2246 [M + H] ⁺

According to Example 236 4- (3-butyl-2-methyl -3H- imidazo [4,5-b] pyridin-5-yl) pyridin-2-amine General Procedure IX, starting from the preparation 6a, Example 236 was obtained. HRMS (IT-TOF, ESI) m / z: Calculated value of C ₁₆ H ₁₉ N ₅ 281.1640, measured value: 282.710 [M + H] ⁺

Example 237 4- [3- (2-Cyclohexylethyl) -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl] pyridin-2-amine Following general procedure IX, starting from preparation 6b Thus, Example 237 was obtained. HRMS (TOF, ESI) m / z: Calculated value for C ₂₀ H ₂₅ N ₅ 335.2110, found value: 336.2184. [M + H] ⁺

Example 238 4- [3- (Cyclopropylmethyl) -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl] pyridin-2-amine Following general procedure IX, starting from preparation 6c. Example 238 was obtained. HRMS (TOF, ESI) m / z: Calculated value of C ₁₆ H ₁₇ N ₅ 279.1484, measured value: 280.1562 [M + H] ⁺

Example 239 4- [3- (But-3-en-1-yl) -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl] pyridin-2-amine According to general procedure IX, Example 239 was obtained starting from preparation 6d. HRMS (IT-TOF, ESI) m / z: Calculated value of C ₁₆ H ₁₇ N ₅ 279.1484, measured value: 280.1552 [M + H] ⁺

Example 240 4- [3- (3,3-Difluorocyclobutyl) -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl] -6-fluoropyridin-2-amine General Procedure X To give Example 240 starting from Preparation 7a using 6-amino-4-bromo-2-fluoropyridine as the appropriate aryl halide. HRMS (TOF, ESI) m / z: Calculated value of C ₁₆ H ₁₄ F ₃ N ₅ 333.1201, actual value: 334.1270 [M + H] ⁺

Example 241 4- (3-Cyclopropyl-2-methyl-3H-imidazo [4,5-b] pyridin-5-yl) -3,6-difluoropyridin-2-amine Following general procedure X, preparation 6e Starting from, Example 241 was obtained using 6-amino-4-bromo-2,5-difluoropyridine as the appropriate aryl halide. HRMS (TOF, ESI) m / z: Calculated value of C ₁₅ H ₁₃ F ₂ N ₅ 301.1139, measured value: 302.1202 [M + H] ⁺

Example 242 4- (3-Cyclopropyl-2-methyl-3H-imidazo [4,5-b] pyridin-5-yl) -3,5-difluoropyridine-2,6-diamine Prepared according to general procedure X Starting from product 6f, Example 242 was obtained using 4-bromo-2,6-diamino-3,5-difluoropyridine as the appropriate aryl halide. HRMS (TOF, ESI) m / z: Calculated value for C ₁₅ H ₁₄ F ₂ N ₆ 316.1248, found value: 317.1310 [M + H] ⁺

Pharmacological test
Example A: Kinase TR-FRET assay Inhibition of enzyme activity of human kinase was evaluated in a time-resolved fluorescence resonance energy transfer (TR-FRET) assay in a 384 well reaction plate. In this assay, full-length human kinases (DYRK1A (NM_001396, ref. 04-130; 2.0 ng / μL), DYRK1B (NM_004714, ref. 04-131; 1.2 ng / μL), CLK1 (NM_001162407) from Carna Biosciences. ref. 04-126; 0.7 ng / μL), CDK9 (NM_001261, ref. 04-110; 0.9 ng / μL), or GSK3β (NM_001146156, ref. 04-141; 2.0 ng / μL)). , 50 mM HEPES (pH 7.4), 1 mM EGTA, 10 mM MgCl ₂ , ATP (Sigma A2383, 10 μM) and UL Light ™ labeled human myelin basic protein in a reaction buffer consisting of 2 mM DTT and 0.01% Tween 20 (MBP) Peptide with substrate (Perkin Elmer TRF0109,100nM), and for 40 minutes at room temperature (DYRK1A and DYRK1B) or 100 minutes (CLK1, CDK9 and GSK3 [beta) incubation. Test compounds of the invention were added to the reaction buffer in a concentration range of 0.1 nM to 30 μM. After stopping the reaction by adding EDTA (Sigma E7889, 10 mM), a europium labeled mouse monoclonal antibody that recognizes phospho-Thr232 in MBP (Perkin Elmer TRF0201, 1 nM) was added. After 1 hour, the reaction plate was read using a fluorescence reader (EnVision®, Perkin Elmer) at 620 nm and 650 nm (excitation at 340 nm): if the europium donor fluorophore was excited by 340 nm light, the acceptor Energy transfer to (620 nm) occurs, which then emits 665 nm light. Therefore, the activity (and thus inhibition) of DYRK1A kinase activity is measured by the relative intensity of luminescence. The IC ₅₀ was calculated from the concentration-activity curve as the concentration of test compound required to inhibit the kinase activity by 50%. Results are presented in Table 1.

Example B: Kinase ADP assay ATP (Sigma Aldrich A7699) is used to accumulate the His-TEV-DYRK1A kinase domain using the accumulation of ADP produced during phosphorylation of the peptide substrate Woodtide (Zinsser Analytic). The activity of aa 127-485) was measured. Enzymatic reactions were performed in assay buffer (pH 7.4) containing 15 mM Hepes; 20 mM NaCl; 1 mM EGTA; 10 mM MgCl 2; 0.02% Tween 20 and 0.1 mg / mL bovine-y-globulin. The test compound of the present invention was added to the reaction buffer in a concentration range for 10 minutes at 30 ° C. in the presence of 20 nM DYRK1A enzyme, 40 μM peptide substrate and 20 μM ATP. Detection reagent (DiscoverRx 90-0083), ADP Hunter Plus Reagent A, and then ADP Hunter Plus Reagent B were added. Subsequently, after 20 minutes of incubation at 30 ° C., ADP Hunter Plus Stop Solution was added. The fluorescence intensity was measured at 590 nm. The IC ₅₀ was calculated from the concentration-activity curve as the concentration of test compound required to inhibit the kinase activity by 50%. Results are presented in Table 1.

Example C: Cellular DYRK1A Autophosphorylation Assay On day 0, human U2-OS osteosarcoma cells were seeded in 12-well culture plates (100,000 cells / well) and 50 units / mL penicillin, 50 μg / mL In 1 mL of McCoy's 5A (modified) medium containing GlutaMAX ™ (Gibco 36600) supplemented with streptomycin, 10 mM Hepes buffer (pH = 7.4) and 10% fetal calf serum (FCS, Sigma F7524) Incubated at 37 ° C. in the presence of 5% CO ₂ . On day 1, 150 ng, 0.3% lipofectamine containing cDNA sequence containing GlutaMAX ™ (Gibco 51985), a full-length wild type human DYRK1A with HA tag (NM — 001396). The medium was replaced with 500 μL of Optimem medium containing (Invitrogen 18324-020) and 0.6% Plus Reagent (Invitrogen catalog number 11514-015). After 5 hours, the medium was replaced with 900 μL of McCoy's 5A (modified) medium containing GlutaMAX ™ (Gibco 36600). On day 2, cells were exposed to a concentration range of the test compound of the invention for 5 hours. The cells were then washed with phosphate buffered saline and 150 mM NaCl, 20 mM Tris-HCl (pH 7.4), 1% triton X-100, 1 mM EGTA, 1 mM EDTA, and protease (1% v / Cells were lysed in a lysis buffer consisting of v; 539134; Calbiochem) and phosphatase (1% v / v; 524625; Calbiochem) inhibitor cocktail (50 μL lysis buffer / well). Relative levels of phospho-Ser520-DYRK1A were assayed using either Western blotting or Mesoscale ELISA platform. For analysis by Western blot, lysates were diluted with Laemmli sample buffer (Bio-Rad) containing 5% v / v β-mercaptoethanol, heated at 95 ° C. for 5 minutes, and either Tris-Glycine gel or NuPage Separated on Bis-Tris gel (Novex; Invitrogen). A biotinylated molecular weight standard (Cell Signaling Technology) was included in all gels. The protein was transferred to a nitrocellulose membrane (Hybond, ECL; Amersham), which was blocked with Tris buffered saline containing 5% milk / 0.1% tween 20 (TBST) and overnight at 4 ° C. Probing with anti-phospho-Ser520-DYRK1A antibody (Eurogentec SE6974-75; 0.23 μg / mL in 5% BSA) or anti-DYRK1A antibody (Abnova H0000001859; 0.5 μg / mL in 5% milk). Peroxidase-conjugated secondary antibody was diluted with 5% milk and applied to the membrane for 1 hour at 20 ° C. Chemiluminescence detection was performed using an ECL plus western detection kit (Amersham) and recorded with an ECL plus hyperfilm (Amersham). Blots were scanned using a Bio-Rad GS-800 calibrated densitometer and quantitative analysis of western blots was performed using TotalLab software (Amersham). IC ₅₀ values for inhibition of phospho-Ser520-DYRK1A were calculated from dose-response curves plotting the ratio between phospho Ser520-DYRK1A signal and total DYRK1A signal at each concentration. For analysis by Mesoscale ELISA, lysates were transferred for 1 hour with shaking at RT into BSA-blocked ELISA plates pre-bound with anti-HA capture antibody (Novus biologic NB600-364; 15 μg / mL). Anti-phospho-Ser520-DYRK1A antibody (Eurogentec SE6974-75; 2.3-3.0 mg / mL) and anti-DYRK1A antibody (Abnova H0000001859; 3 μg / mL) were then added for 1 hour at RT, followed by Sulfa- TAG anti-rabbit detection antibody (ref MSD R32AB; 1 μg / mL) and Sulfa-TAG anti-mouse detection antibody (ref MSD R32-AC-1; 1 μg / mL) were added. After an additional hour, Read Buffer was added and the plate was read on a Sector Imager 2400 (Mesoscale). IC ₅₀ values for inhibition of phospho-Ser520-DYRK1A were calculated from dose-response curves. The results showed that the compounds of the present invention are potent inhibitors of cellular DYRK1A Ser520 autophosphorylation. Results are presented in Table 1.

Example D: Pharmacodynamic assay in tumor xenografts for inhibition of DYRK1A autophosphorylation For the pharmacodynamic test of inhibition of DYRK1A autophosphorylation, female SCID mice were RS4; 11 human acute lymphoblastic leukemia cells. Was injected subcutaneously. When tumors reached a size of 200-300 mm ³ , mice were randomized into 3 homogeneous groups and a single oral dose of a compound of the invention up to a dose of 100 mg / kg. At various time points after treatment (typically 2 and 6 hours), treated and control mice are sacrificed, tumors are excised, and 150 mM NaCl, 20 mM Tris-HCl (pH 7.4), 1 Protein in a tissue lysis buffer consisting of% triton X-100, 1 mM EGTA, 1 mM EDTA, and protease (1% v / v; 539134; Calbiochem) and phosphatase (1% v / v; 524625; Calbiochem) inhibitor cocktail Extracted. Western blotting was used to assay the relative levels of phospho-Ser520-DYRK1A. For this, the lysate is diluted with Laemmli sample buffer (Bio-Rad) containing 5% v / v β-mercaptoethanol, heated at 95 ° C. for 5 minutes, and either Tris-Glycine gel or NuPage Bis-Tris. Separated on a gel (Novex; Invitrogen). A biotinylated molecular weight standard (Cell Signaling Technology) was included in all gels. The protein was transferred to a nitrocellulose membrane (Hybond, ECL; Amersham), which was blocked with Tris buffered saline containing 5% milk / 0.1% tween 20 (TBST) and overnight at 4 ° C. Probing with anti-phospho-Ser520-DYRK1A antibody (Eurogentec SE6974-75; 0.23 μg / mL in 5% BSA) or anti-DYRK1A antibody (Abnova H0000001859; 0.5 μg / mL in 5% milk). Peroxidase-conjugated secondary antibody was diluted with 5% milk and applied to the membrane for 1 hour at 20 ° C. Chemiluminescence detection was performed using an ECL plus western detection kit (Amersham) and recorded with an ECL plus hyperfilm (Amersham). Blots were scanned using a Bio-Rad GS-800 calibrated densitometer and quantitative analysis of western blots was performed using TotalLab software (Amersham). The ratio between phospho-Ser520-DYRK1A signal and total DYRK1A signal at each dose was used to calculate the percent inhibition of phospho-Ser520-DYRK1A compared to the control tumor. The results showed that the compounds of the present invention are potent inhibitors of tumor DYRK1A Ser520 autophosphorylation.

Example E: Efficacy study in tumor xenografts For nude tumor balb / c nu / nu mice were injected subcutaneously with A2780 human ovarian carcinoma cells for anti-tumor efficacy studies. When the tumor reaches a size of about 150 mm ³ , the mice are randomized into 8 homogeneous groups, and once a day for 2 weeks, the compounds of the invention are administered orally at concentrations up to a dose of 75 mg / kg. Was treated. Antitumor efficacy was monitored by measuring tumor size at least twice a week using calipers, and body weight was recorded to record possible general toxicity. Tumor growth inhibition rate (TGI) on a given day is given by the formula: (1- [RTV (treated) / RTV (untreated)]) × 100 (where RTV = start of treatment given day) Relative tumor volume). The results showed that the compounds of the present invention are potent inhibitors of tumor growth.

Example F: Pharmaceutical composition: Tablets Compound selected from Examples 1 to 242 1000 tablets containing a dose of 5 mg
5g
20g wheat starch
Corn starch 20g
Lactose 30g
Magnesium stearate 2g
Silica 1g
Hydroxypropylcellulose 2g

Claims (33)

Formula (I):

(Where
R ₁ represents a cyano group, a halogen atom, or a linear or branched (C ₁ -C ₆ ) alkyl group optionally substituted by 1 to 3 halogen atoms,
◆ R ₂ is hydrogen, straight chain or branched chain (C ₁ -C ₆ ) alkyl group, straight chain or branched chain (C ₂ -C ₆ ) alkenyl group, straight chain or branched chain (C ₂ -C _{6) alkynyl,} Cy 1, - _(C 1 -C ₆₎ alkylene - _[O] n -Cy ₁ group, - _(C 1 -C ₆₎ alkenylene - _[O] n -Cy ₁ group, - _{(C 1} -C ₆₎ alkylene -NR-Cy ₁ group, - _(C 1 -C ₆₎ alkylene--S-Cy ₁ group, - _(C 0 -C ₆₎ alkylene _-Cy 2 -Cy ₁ group, or -Cy ₂ - It is understood that the alkyl and alkylene moieties defined above representing a (C ₁ -C ₆ ) alkylene-Cy ₁ group may be linear or branched,
◆ R represents hydrogen, or a linear or branched (C ₁ -C ₆ ) alkyl group,
◆ n is an integer equal to 0 or 1,
◆ R ₃ is a hydrogen atom, a halogen atom, —NR ₆ R ₆ ′, —NH— (C ₀ -C ₆ ) alkylene-Cy ₃ , —NH—CO— (C ₀ -C ₆ ) alkylene-Cy ₃ , _{-NH-CO- (C 0 -C 6} ) alkylene -O-Cy _3,
◆ R ₄ and R ₅ each independently represent a hydrogen or halogen atom,
R ₆ and R ₆ ′ each independently of the other represent hydrogen or a linear or branched (C ₁ -C ₆ ) alkyl group;
Cy ₁ , Cy ₂ and Cy ₃ each independently represent a cycloalkyl group, a heterocycloalkyl group, an aryl or a heteroaryl group,
“Aryl” means a phenyl, naphthyl, biphenyl or indenyl group;
“Heteroaryl” is composed of 5 to 10 ring members having at least one aromatic moiety and containing 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen Means any monocyclic or bicyclic group,
“Cycloalkyl” is any monocyclic or bicyclic, non-aromatic, carbocyclic group containing from 3 to 11 ring members, which may include fused, bridged or spiro ring systems. Means
“Heterocycloalkyl” is composed of 3 to 10 ring members which may include fused, bridged or spiro ring systems and is selected from oxygen, sulfur, SO, SO ₂ and nitrogen 1-3 Means any monocyclic or bicyclic, non-aromatic, fused or spiro group containing 1 heteroatom,
“— (C ₀ -C ₆ ) alkylene-” refers to either a covalent bond (—C ₀ alkylene-) or an alkylene group containing 1, 2, 3, 4, 5 or 6 carbon atoms. Is understood and
Aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups as defined above, as well as alkyl, alkenyl, alkynyl, alkylene, alkenylene are linear or branched (C ₁ -C ₆ ) alkyl, linear or branched Branched (C ₂ -C ₆ ) alkenyl group, linear or branched (C ₂ -C ₆ ) alkynyl group, linear or branched (C ₁ -C ₆ ) alkoxy, linear or branched ( C ₁ -C ₆₎ alkyl -S-, hydroxy, if oxo (or suitable, N- oxide), nitro, cyano, -C (O) -OR ', - C (O) -R', - O- C (O) —R ′, —C (O) —NR′R ″, —NR′—C (O) —R ″, —NR′R ″, linear or branched (C ₁ — C ₆₎ polyhaloalkyl, difluoromethoxy, trifluoromethoxy methemoglobin R ′ and R ″ can be independently of one another a hydrogen atom, or a straight or branched chain that is substituted, It is understood to represent a chain (C ₁ -C ₆ ) alkyl group)
And their enantiomers and diastereoisomers, and their addition salts with pharmaceutically acceptable acids or bases. The compound of formula (I) according to claim 1, wherein R ₁ represents a methyl or cyano group. The compound represented by formula (I) according to claim 1 or 2, wherein R ₄ and R ₅ each represent a hydrogen atom. R ₃ is, represents a NH ₂ group, the compound represented by the formula one claim (I) of claims 1-3. The compound represented by formula (I) according to one of claims 1 to ₃ , wherein R ₃ represents a hydrogen atom. R ₂ represents hydrogen, a linear or branched (C ₁ -C ₆ ) alkyl group, a linear or branched (C ₂ -C ₆ ) alkenyl group, a linear or branched chain (C ₂ -C _6). ) alkynyl, - _(C 1 -C ₆₎ alkylene -O-Cy ₁ group, - _(C 1 -C ₆₎ alkenylene - _[O] n -Cy ₁ group, - _(C 1 -C ₆₎ alkylene -NR -Cy ₁ group,-(C ₁ -C ₆ ) alkylene-S-Cy ₁ group,-(C ₀ -C ₆ ) alkylene-Cy ₂ -Cy ₁ group, or -Cy _2- (C ₂ -C ₆ ) The formula (1) according to one of claims 1 to 5, which represents an alkylene-Cy ₁ group, wherein the alkyl and alkylene moieties defined above may be linear or branched. A compound represented by I). R ₂ is Cy ₁ , — (C ₁ -C ₆ ) alkylene-Cy ₁ group, — (C ₀ -C ₆ ) alkylene-Cy ₂ -Cy ₁ group, or —Cy ₂ — (C ₁ -C ₆ ). an alkylene -Cy ₁ group, the compound represented by the formula one claim (I) of claims 1-5. R ₂ is:
A cycloalkyl group,
Or-(C ₁ -C ₆ ) alkylene-cycloalkyl, or-(C ₁ -C ₆ ) alkylene-phenyl group,
Or, -cycloalkylene-phenyl group, or -cycloalkylene- (C ₁ -C ₆ ) alkylene-phenyl group,
8. Compounds of formula (I) according to claim 7, wherein the cycloalkyl, cycloalkylene and phenyl groups thus defined may be optionally substituted according to the definitions already mentioned. R ₂ represents a linear or branched (C ₁ -C ₆ ) alkyl group, the alkyl group thus defined may be optionally substituted according to the definition of formula (I) A compound represented by the formula (I) according to one of 1 to 5. R ₂ is, - _(C 1 -C ₆₎ represents an alkylene -O-Cy ₁ group, the compound represented by the formula one claim (I) of claims 1-5. 11. R ₂ represents a — (C ₁ -C ₆ ) alkylene-O-pyridinyl group, the pyridinyl group thus defined may be optionally substituted according to the definition of formula (I) Compounds of formula (I) as described. The following groups:
4- [2-methyl-3- (3-phenylcyclobutyl) -3H-imidazo [4,5-b] pyridin-5-yl] pyridine-2,6-diamine,
4- [3- (3,3-difluorocyclobutyl) -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl] pyridine-2,6-diamine,
4- (3- {2-[(6-Fluoropyridin-2-yl) oxy] ethyl} -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl) pyridin-2,6- Diamine,
4- {3-[(1R, 2R) -2-benzylcyclopropyl] -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl} pyridin-2,6-diamine,
4- [3- (3-fluorocyclobutyl) -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl] pyridine-2,6-diamine,
4- (3-hexyl-2-methyl-3H-imidazo [4,5-b] pyridin-5-yl) pyridine-2,6-diamine,
4- (3-cyclobutyl-2-methyl-3H-imidazo [4,5-b] pyridin-5-yl) pyridine-2,6-diamine,
4- [3- (2-{[6- (Difluoromethyl) pyridin-2-yl] oxy} ethyl) -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl] pyridine-2 , 6-diamine,
4- [3- (5-Methoxy-2,3-dihydro-1H-inden-2-yl) -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl] pyridin-2,6 A diamine,
4- (3-ethyl-2-methyl-3H-imidazo [4,5-b] pyridin-5-yl) pyridine-2,6-diamine,
4- [2-Methyl-3- (2-{[6- (trifluoromethyl) pyridin-2-yl] oxy} ethyl) -3H-imidazo [4,5-b] pyridin-5-yl] pyridine- 2,6-diamine,
4- {3- [2- (2-methoxycyclohexyl) ethyl] -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl} pyridin-2,6-diamine,
4- (2-methyl-3-pentyl-3H-imidazo [4,5-b] pyridin-5-yl) pyridine-2,6-diamine,
4- (3-cyclohexyl-2-methyl-3H-imidazo [4,5-b] pyridin-5-yl) pyridine-2,6-diamine,
4- {2-methyl-3- [3- (methylsulfanyl) propyl] -3H-imidazo [4,5-b] pyridin-5-yl} pyridin-2,6-diamine,
4- {3-[(1R, 2S) -2-benzylcyclopropyl] -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl} pyridin-2,6-diamine,
4- {2-methyl-3- [2- (2-methylphenyl) ethyl] -3H-imidazo [4,5-b] pyridin-5-yl} pyridine-2,6-diamine,
4- (3- {2-[(6-chloropyridin-2-yl) oxy] ethyl} -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl) pyridine-2,6- Diamine,
4- (3-{(2R) -2-[(6-fluoropyridin-2-yl) oxy] propyl} -2-methyl-3H-imidazo [4,5-b] pyridin-5-yl) pyridine- 2,6-diamine,
4- [2-methyl-3- (2,2,2-trifluoroethyl) -3H-imidazo [4,5-b] pyridin-5-yl] pyridine-2,6-diamine,
3-cyclopentyl-5- (2,6-diaminopyridin-4-yl) -3H-imidazo [4,5-b] pyridine-2-carbonitrile 4- (3-cyclopropyl-2-methyl-3H-imidazo [4,5-b] pyridin-5-yl) pyridine-2,6-diamine,
A compound of formula (I) according to claim 1, selected from: their enantiomers and diastereoisomers, and their addition salts with pharmaceutically acceptable acids or bases. The compound of formula (I) according to claim 1, which is 4- (3-ethyl-2-methyl-3H-imidazo [4,5-b] pyridin-5-yl) pyridine-2,6-diamine. . The compound of formula (I) according to claim 1, which is 4- (2-methyl-3-pentyl-3H-imidazo [4,5-b] pyridin-5-yl) pyridine-2,6-diamine. . 4- {2-Methyl-3- [2- (2-methylphenyl) ethyl] -3H-imidazo [4,5-b] pyridin-5-yl} pyridine-2,6-diamine. Compounds of formula (I) as described. 4. [4-Methyl-3- (2,2,2-trifluoroethyl) -3H-imidazo [4,5-b] pyridin-5-yl] pyridin-2,6-diamine. Compounds of formula (I) as described. A compound of formula (I) which is 4- (3-cyclopropyl-2-methyl-3H-imidazo [4,5-b] pyridin-5-yl) pyridine-2,6-diamine. A process for preparing a compound of formula (I) according to claim 1, wherein the compound of formula (II):

Wherein A represents a halogen atom or a linear or branched (C ₁ -C ₆ ) alkyl group optionally substituted by 1 to 3 halogen atoms, and X represents a halogen atom. And R ₂ is as defined in formula (I))
A compound represented by
A compound of formula (II) is represented by formula (III):

(Where:
R _B1 and R _B2 represent hydrogen, a linear or branched (C ₁ -C ₆ ) alkyl group, or R _B1 and R _B2 are optionally methylated with an oxygen atom carrying them. Form a ring
R _B3 represents hydrogen or a group NH ₂ ;
R ₄ and R ₅ are as defined in formula (I))
For coupling with a compound of formula (IV):

(In the formula, A represents a halogen atom or a linear or branched (C ₁ -C ₆ ) alkyl group optionally substituted with 1 to 3 halogen atoms, and R _B3 represents hydrogen or a group; NH ₂ and R ₂ , R ₄ and R ₅ are as defined in formula (I))
To obtain a compound represented by
The compound represented by formula (IV) is
When A represents halogen, reaction with Et ₄ NCN may give a compound of formula (I) (wherein R ₁ = —CN) or R ₂ is linear or branched When representing a HO- (C ₁ -C ₆ ) alkylene group, subjected to aromatic nucleophilic substitution and / or subjected to acylation in the presence of an acid derivative;
You may obtain the compound shown by a formula (I),
The compounds of formula (I) may be purified by conventional separation techniques, which are optionally converted to their addition salts with pharmaceutically acceptable acids or bases, which are conventionally Optionally separated into their isomers by the separation technique of
Depending on the needs of the synthesis, at any point considered appropriate in the course of the above process, certain groups (hydroxy, amino ...) of the reagent or synthesis intermediate are protected and then deprotected. A process characterized in that it is understood that it is also good. A process for the preparation of a compound of formula (I) according to claim 1, wherein formula (II '):

Wherein A ′ represents a linear or branched (C ₁ -C ₆ ) alkyl group optionally substituted with 1 to 3 halogen atoms, and X represents a halogen atom.
A compound represented by
A compound of formula (II ′) is represented by formula (III):

(Where:
R _B1 and R _B2 represent hydrogen, a linear or branched (C ₁ -C ₆ ) alkyl group, or R _B1 and R _B2 are optionally methylated with an oxygen atom carrying them. Form a ring
R _B3 represents hydrogen or a group NH ₂ ;
R ₄ and R ₅ are as defined in formula (I))
For coupling with a compound of formula (IV ′):

(Where:
A ′ represents a linear or branched (C ₁ -C ₆ ) alkyl group optionally substituted by 1 to 3 halogen atoms,
R _B3 represents hydrogen or a group NH ₂ ;
R ₄ and R ₅ are as defined in formula (I))
To obtain a compound represented by
The compound of formula (IV ′) is:
A) Subjected to nucleophilic substitution in the presence of a compound of formula R ₂ —NH ₂ , wherein R ₂ is as defined in formula (I), formula (V ′):

(Where:
A ′ represents a linear or branched (C ₁ -C ₆ ) alkyl group optionally substituted by 1 to 3 halogen atoms,
R _B3 represents hydrogen or a group NH ₂ ;
R ₂ , R ₄ and R ₅ are as defined in formula (I))
To obtain a compound represented by
The compound of formula (V ′) undergoes an intramolecular reaction (ring closure) in an acidic medium to give a compound of formula (I),
B) or formula (VI ′):

(Where:
R is a linear or branched (C ₁ -C ₆ ) alkyl group, an optionally substituted aryl, or a linear or branched polyhalogenated (C ₁ -C ₆ ) alkyl group;
A ′ represents a linear or branched (C ₁ -C ₆ ) alkyl group optionally substituted by 1 to 3 halogen atoms,
R _B3 represents hydrogen or a group NH ₂ ;
R ₄ and R ₅ are as defined in formula (I))
Converted to the corresponding iminosulfonate derivative represented by
The compound of formula (VI ′) is further nucleophilic substituted in the presence of a compound of formula R ₂ —NH ₂ , wherein R ₂ is as defined in formula (I). In formula (VII ′):

(Where:
A ′ represents a linear or branched (C ₁ -C ₆ ) alkyl group optionally substituted by 1 to 3 halogen atoms,
R _B3 represents hydrogen or a group NH ₂ ;
R ₂ , R ₄ and R ₅ are as defined in formula (I))
To obtain a compound represented by
The compound represented by the formula (VII ′) undergoes an intramolecular organometallic coupling reaction, and is represented by the formula (I) (wherein the definition of R ₁ is limited to one of A ′) One of obtaining a compound,
The compounds of formula (I) may be purified by conventional separation techniques, which are optionally converted to their addition salts with pharmaceutically acceptable acids or bases, which are conventionally Optionally separated into their isomers by the separation technique of
Depending on the needs of the synthesis, at any point considered appropriate in the course of the above process, certain groups (hydroxy, amino ...) of the reagent or synthesis intermediate are protected and then deprotected. A process characterized in that it is understood that it is also good.   18. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 17 or an addition salt thereof with a pharmaceutically acceptable acid or base, comprising one or more pharmaceuticals A pharmaceutical composition in combination with an acceptable excipient.   21. A pharmaceutical composition according to claim 20 for use in the treatment of cancer, neurodegenerative disorders or metabolic disorders.   Cancer is acute megakaryoblastic leukemia (AMKL), acute lymphoblastic leukemia (ALL), ovarian cancer, pancreatic cancer, gastrointestinal stromal tumor (GIST), osteosarcoma (OS), colorectal carcinoma (CRC) 22. A pharmaceutical composition according to claim 21, selected from: neuroblastoma and glioblastoma.   The pharmaceutical composition according to claim 21, wherein the neurodegenerative disorder is selected from Alzheimer's disease, Parkinson's disease and Huntington's disease, Down's syndrome, mental retardation, and movement disorder.   21. Use of a pharmaceutical composition according to claim 20 in the manufacture of a medicament intended to treat cancer, neurodegenerative disorders or metabolic disorders.   Cancer is acute megakaryoblastic leukemia (AMKL), acute lymphoblastic leukemia (ALL), ovarian cancer, pancreatic cancer, gastrointestinal stromal tumor (GIST), osteosarcoma (OS), colorectal carcinoma (CRC) 25. Use according to claim 24, selected from: neuroblastoma and glioblastoma.   25. Use according to claim 24, wherein the neurodegenerative disorder is selected from Alzheimer's disease, Parkinson's disease and Huntington's disease, Down's syndrome, mental retardation, and movement disorders.   Addition of a compound of formula (I) according to one of claims 1 to 17 or a pharmaceutically acceptable acid or base thereof for use in the treatment of cancer, neurodegenerative disorders or metabolic disorders salt.   A compound of formula (I) according to one of claims 1 to 17, or a pharmaceutically acceptable acid thereof, in the manufacture of a medicament intended to treat cancer, neurodegenerative disorders or metabolic disorders Use of addition salts with bases.   A compound represented by the formula (I) according to any one of claims 1 to 17, a genotoxic agent, a mitotic toxin, an antimetabolite, a proteasome inhibitor, a kinase inhibitor, a signal transduction pathway inhibitor, a phosphatase A combination with an anticancer agent selected from an inhibitor, an apoptosis inducer and an antibody.   30. A pharmaceutical composition comprising a combination according to claim 29, in combination with one or more pharmaceutically acceptable excipients.   30. A combination according to claim 29 for use in the treatment of cancer.   30. Use of a combination according to claim 29 in the manufacture of a medicament for use in the treatment of cancer.   A compound of formula (I) according to any one of claims 1 to 17 for use in the treatment of a cancer in need of radiation therapy.